TW201837021A - Chemical compounds as inhibitors of interleukin-1 activity - Google Patents

Chemical compounds as inhibitors of interleukin-1 activity Download PDF

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Publication number
TW201837021A
TW201837021A TW107102246A TW107102246A TW201837021A TW 201837021 A TW201837021 A TW 201837021A TW 107102246 A TW107102246 A TW 107102246A TW 107102246 A TW107102246 A TW 107102246A TW 201837021 A TW201837021 A TW 201837021A
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Taiwan
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alkyl
cycloalkyl
halogen
heterocyclyl
heteroaryl
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TW107102246A
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Chinese (zh)
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傑佛瑞 艾倫 史丹福
詹姆士 馬文 畢爾
梨尼 琳 特洛斯
克里斯多福 麥克布萊德
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美商傑庫爾醫療股份有限公司
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Publication of TW201837021A publication Critical patent/TW201837021A/en

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Abstract

The present disclosure relates to novel sulfonylurea and sulfonyl thiourea compounds and related compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1[beta] and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.

Description

作為介白素-1活性抑制劑之化合物Compounds as interleukin-1 activity inhibitors

本發明係關於新穎磺醯脲及磺醯基硫脲化合物及相關化合物及其在治療對諸如IL-1β及IL-18等細胞介素之調節、NLRP3之調節或NLRP3或發炎過程之相關組分之活化之抑制有反應的疾病或病況中之用途。The present invention relates to novel sulfonylurea and sulfonylurea thiourea compounds and related compounds and related components in the treatment of cytokines such as IL-1β and IL-18, NLRP3, or NLRP3 or inflammatory processes The use in activation of a reactive disease or condition.

NOD樣受體(NLR)家族、含熱蛋白結構域之蛋白質3 (NLRP3)發炎體係發炎過程之組分，且其失常活化係遺傳病症(例如隱熱蛋白相關週期症候群(CAPS))及複雜疾病(例如多發性硬化、2型糖尿病、阿茲海默氏病(Alzheimer's disease)及動脈粥樣硬化)之致病機制。 NLRP3係感測某些發炎信號之細胞內受體蛋白。活化時，NLRP3結合至含有半胱天冬酶活化及招募結構域之細胞凋亡相關之斑點樣蛋白質(ASC)。NLRP3 - ASC複合物隨後聚合以形成大的聚集物，稱作ASC斑點。聚合之NLRP3-ASC進而與半胱胺酸蛋白酶半胱天冬酶-1相互作用以形成複合物，稱作發炎體。此引起半胱天冬酶-1之活化，該半胱天冬酶-1將促炎性細胞介素IL-1β及IL-18裂解成其活性形式並介導一種類型之發炎細胞死亡，稱作細胞焦亡(pyroptosis)。ASC斑點亦可招募並活化半胱天冬酶-8，其可處理促-IL-1β及促-IL-18並觸發細胞凋亡性細胞死亡。 半胱天冬酶-1將促-IL-1β及促-IL-18裂解成其活性形式，其係自細胞分泌。活性半胱天冬酶-1亦裂解gasdermin-D以觸發細胞焦亡。半胱天冬酶-1經由細胞焦亡性細胞死亡路徑之其控制，亦介導警報素(alarmin)分子(例如IL-33及高遷移率族蛋白1 (HMGB1))之釋放。半胱天冬酶-1亦裂解細胞內IL-1R2，從而引起其降解並容許IL-1α之釋放。在人類細胞中，半胱天冬酶-1亦可控制IL-37之處理及分泌。多種其他半胱天冬酶-1受質(例如細胞骨架及醣酵解路徑之組分)可促使半胱天冬酶-1依賴性發炎。 NLRP3依賴性ASC斑點釋放至細胞外環境中，其中其可活化半胱天冬酶-1，誘導半胱天冬酶-1受質之處理並傳播發炎。 源自NLRP3發炎體活化之活性細胞介素係發炎之重要驅動子且與其他細胞介素路徑相互作用以形成對感染及損傷之免疫反應。舉例而言，IL-1β信號傳導誘導促發炎細胞介素IL-6及TNF之分泌。IL-1β及IL-18與IL-23協同作用以誘導在不存在T細胞受體結合下由記憶CD4 Th17細胞及γδ T細胞產生IL-17。IL-18及IL-12亦協同作用以誘導自驅動Th1反應之記憶T細胞及NK細胞產生IFN-γ。 其他細胞內模式識別受體(PRR)亦能夠形成發炎體。該等受體包括其他NLR家族成員，例如NLRP1及NLRC4，以及非NLR PRR，例如黑色素瘤2 (AIM2)及干擾素γ可誘導蛋白16 (IFI16)中不存在之雙鏈DNA (dsDNA)感測器。NLRP3依賴性IL-1β處理亦可由半胱天冬酶-11下游之間接非正規路徑活化。 遺傳CAPS疾病穆-韋二氏症候群(Muckle-Wells syndrome，MWS)、家族性冷因性自體發炎症候群及新生兒發作性多系統發炎性疾病係由NLRP3之功能獲得型突變引起，由此將NLRP3定義為發炎過程之關鍵組分。NLRP3亦參與多種複雜疾病(顯著地，包括代謝失調，例如2型糖尿病、動脈粥樣硬化、肥胖症及痛風)之致病機制。 出現NLRP3在中樞神經系統疾病中之作用，且亦已顯示肺病受NLRP3影響。此外，NLRP3在肝病、腎病及老化之發生中起作用。該等相關性中之許多係使用具有組成型NLRP3活化之小鼠定義，但亦瞭解該等疾病中NLRP3之特異性活化。在2型糖尿病中，小島類澱粉多肽在胰臟中之沈積會活化NLRP3及IL-1β信號傳導，從而引起細胞死亡及發炎。 需要提供具有改良之藥理學及/或生理及或物理化學性質之化合物及/或提供已知化合物之有用替代物之彼等。NOD-like receptor (NLR) family, a component of the inflammatory process of the protein 3 (NLRP3) inflammation system, and abnormal activation of genetic disorders (such as cryptothermia-related cycle syndrome (CAPS)) and complex diseases (E.g. multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis). NLRP3 is an intracellular receptor protein that senses certain inflammatory signals. Upon activation, NLRP3 binds to an apoptosis-related spot-like protein (ASC) containing a caspase activation and recruitment domain. The NLRP3-ASC complex is then polymerized to form large aggregates, called ASC spots. The aggregated NLRP3-ASC in turn interacts with the cysteine protease caspase-1 to form a complex called an inflammasome. This causes the activation of caspase-1, which cleaves the pro-inflammatory interleukins IL-1β and IL-18 into their active forms and mediates the death of one type of inflammatory cells, said For cell pyrotosis. ASC spots can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death. Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D to trigger cell death. Caspase-1 controls its path through the dying cell death pathway and also mediates the release of alarmin molecules such as IL-33 and high mobility group protein 1 (HMGB1). Caspase-1 also lyses intracellular IL-1R2, causing its degradation and allowing the release of IL-1α. In human cells, caspase-1 also controls the processing and secretion of IL-37. A variety of other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathway, can contribute to caspase-1 dependent inflammation. NLRP3-dependent ASC spots are released into the extracellular environment, where they can activate caspase-1, induce the caspase-1 to undergo quality treatment and spread inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other interleukin pathways to form an immune response to infection and injury. For example, IL-1β signaling induces the secretion of proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 work synergistically with IL-23 to induce the production of IL-17 from memory CD4 Th17 cells and γδ T cells in the absence of T cell receptor binding. IL-18 and IL-12 also act synergistically to induce the production of IFN-γ by memory T cells and NK cells that drive the Th1 response. Other intracellular pattern recognition receptors (PRRs) can also form inflamed bodies. These receptors include other NLR family members, such as NLRP1 and NLRC4, and non-NLR PRRs, such as double-stranded DNA (dsDNA) sensing, which is absent from melanoma 2 (AIM2) and interferon gamma inducible protein 16 (IFI16). Device. NLRP3-dependent IL-1β treatment can also be activated by an indirect irregular pathway downstream of caspase-11. Genetic CAPS diseases Muckle-Wells syndrome (MWS), familial cold-induced autoinflammation syndrome, and neonatal episodic multi-system inflammatory diseases are caused by NLRP3 function-acquired mutations. NLRP3 is defined as a key component of the inflammatory process. NLRP3 is also involved in the pathogenesis of many complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout. The role of NLRP3 in central nervous system disease has emerged, and lung disease has also been shown to be affected by NLRP3. In addition, NLRP3 plays a role in the occurrence of liver disease, kidney disease and aging. Many of these correlations are defined using mice with constitutive NLRP3 activation, but specific activation of NLRP3 in these diseases is also known. In type 2 diabetes, the deposition of islet amyloid peptides in the pancreas activates NLRP3 and IL-1β signaling, causing cell death and inflammation. There is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties and / or to provide useful alternatives to known compounds.

本發明提供有效抑制發炎體(例如NLRP3發炎體)之化合物。該等化合物亦有效調節介白素。所揭示之化合物具有合意之分子量、物理-化學性質及親脂性，其係有助於達成治療效能並減少不期望易感性之特徵。 本發明提供式I化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5 或N； A1 係NR5 、O、S或C(O)； 每一A2 獨立地係CR5 、C(R5 )2 、N、NR5 、O、S或S(O)2 ； R2 係或； X2 係N或CR5 ； R3 及R4 係H； 每一R5 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；或 兩個R5 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；或 兩個在同一個碳上之R5 可形成側氧基； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5 、O、S或S(O)2 。 本發明提供式Ia化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；或 兩個R5b 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。本發明提供式Ib化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、NH(C1 -C6 烷基)或N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。本發明提供式Ic化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。本發明提供式Id化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、NH(C1 -C6 烷基)或N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。 本發明提供式Ie化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； 每一Rb10 、Rb11 、Rb12 、Rb13 、Rb14 及Rb15 獨立地係H、-OH或側氧基； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、 -NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。本發明提供式If化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。本發明提供式Ig化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。 本發明提供式Ih化合物：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、-OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1-C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代； 其中至少一個R5a2 係-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基；其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。 本發明提供包含本發明化合物、及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物以及醫藥上可接受之載劑、稀釋劑及/或賦形劑的醫藥組合物。 本發明提供治療或預防疾病、病症或病況之方法，其包括如下步驟：投與有效量之本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物為有此需要之個體治療或預防疾病、病症或病況。 本發明提供本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物或本發明醫藥組合物，其用於治療或預防有需要之個體之疾病、病症或病況。 本發明提供本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物之用途，其用於治療或預防有需要之個體之疾病、病症或病況。 本發明提供本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物之用途，其用於製造用於治療或預防疾病、病症或病況之藥劑。 在某些實施例中，該疾病、病症或病況對發炎體之抑制有反應。 在某些實施例中，該疾病、病症或病況對NLRP3發炎體之活化之抑制有反應。 在某些實施例中，該疾病、病症或病況係免疫系統、肝、肺、皮膚、心血管系統、腎系統、胃腸道、呼吸系統、內分泌系統、中樞神經系統之疾病、病症或病況，或係癌症或其他惡性病，或係由病原體引起或與其相關。 本發明提供調節生物靶標之活性之方法，其包含將生物靶標暴露於本發明化合物及其醫藥上可接受之鹽的步驟。 生物靶標可選自由以下組成之群：NLRP3發炎體、IL-6、ΙL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞。The present invention provides compounds that are effective in inhibiting inflammable bodies, such as NLRP3 inflamed bodies. These compounds are also effective in modulating interleukins. The disclosed compounds have desirable molecular weight, physical-chemical properties, and lipophilic properties, which are characteristics that help achieve therapeutic efficacy and reduce undesired susceptibility. The invention provides compounds of formula I:And pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers thereof, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5 Or N; A1 Department of NR5 , O, S or C (O); each A2 Independently CR5 , C (R5 )2 , N, NR5 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5 ; R3 And R4 Department H; each R5 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; or two R5 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; or two in R on the same carbon5 Can form side oxygen; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; each m is independently an integer of 1 to 4; n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5 , O, S, or S (O)2 . The invention provides compounds of formula Ia:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , Each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; or two in R on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; or two R5b Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . The invention provides compounds of formula Ib:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 ,among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , NH (C1 -C6 Alkyl) or N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . The invention provides compounds of formula Ic:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 system; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . The invention provides compounds of formula Id:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 system; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , NH (C1 -C6 Alkyl) or N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . The invention provides compounds of formula Ie:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; Each Rb10 , Rb11 , Rb12 , Rb13 , Rb14 And Rb15 Independently H, -OH or pendant oxygen; R3 And R4 Department H; each R5a1 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . The invention provides compounds of formula If:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; each R5a1 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . The invention provides compounds of formula Ig:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; each R5a1 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . The invention provides compounds of formula Ih:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; each R5a1 Independently H, D, halogen, -OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1-C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; at least one of R5a2 Department-NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups; wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Replace; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . The present invention provides a compound comprising the present invention, and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, and tautomer thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient. Pharmaceutical composition of a tablet. The present invention provides a method for treating or preventing a disease, disorder, or condition, which comprises the steps of administering an effective amount of a compound of the present invention and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, and Tautomers are individuals in need thereof to treat or prevent a disease, disorder, or condition. The present invention provides a compound of the present invention and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer and tautomer thereof, or a pharmaceutical composition of the present invention for use in treating or preventing an individual in need. Disease, illness, or condition. The present invention provides the use of the compound of the present invention and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, which are used to treat or prevent diseases and conditions in individuals in need. Or condition. The present invention provides the use of the compound of the present invention and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, which are used for the manufacture or treatment of diseases, disorders or conditions. Of the potion. In certain embodiments, the disease, disorder, or condition is responsive to the inhibition of an inflamed body. In certain embodiments, the disease, disorder, or condition is responsive to inhibition of activation of the NLRP3 inflammasome. In certain embodiments, the disease, disorder, or condition is a disease, disorder, or condition of the immune system, liver, lung, skin, cardiovascular system, kidney system, gastrointestinal tract, respiratory system, endocrine system, central nervous system, or Cancer or other malignant disease, or caused by or related to a pathogen. The present invention provides a method for modulating the activity of a biological target, comprising the step of exposing the biological target to a compound of the present invention and a pharmaceutically acceptable salt thereof. Biological targets can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33, and Th17 cells.

相關申請案交叉參考 本申請案主張於2017年1月23日提出申請之美國臨時申請案第62/449,431號及於2017年5月1日提出申請之美國臨時申請案第62/492,813號之權益，該等申請案之全部內容之全文皆以引用方式併入本文中。 除非另外指示，否則如上文及貫穿本揭示內容所用之以下術語應理解為具有以下含義：若丟失術語，則以如熟習此項技術者已知之習用術語為準。 如本文中所使用之術語「包括」、「含有」及「包含」係以其開放、非限制意義使用。 本揭示內容中所用之冠詞「一(a及an)」係指該冠詞之文法受詞之一者或一者以上(亦即，係指至少一者)。舉例而言，「要素」意指一個要素或一個以上要素。 除非另外指示，否則本揭示內容中所用之術語「及/或」意指「及」或「或」。 為提供更簡明的說明，本文給出之一些定量表述不經術語「約」限定。應理解，不論是否明確使用術語「約」，本文中給出之每個量皆欲指實際給出值，且由於該給出值之實驗及/或量測條件，其亦欲指該給出值之近似值，其可基於業內一般技術合理地推斷，包括等效物及近似值。每當產率係以百分比給出時，該產率皆係指給出該產率之實體的質量相對於相同實體在特定化學計量條件下可獲得之最大量。除非另外指明，否則以百分比給出之濃度係指質量比。 「患者」係哺乳動物，例如人類、小鼠、大鼠、天竺鼠、狗、貓、馬、牛、豬或非人類靈長類動物，例如猴、黑猩猩、狒狒或恒河猴。「患者」包括人類及動物二者。 術語「抑制劑」係指阻斷或以其他方式干擾特定生物活性之分子，例如化合物、藥物、酶或激素。 術語「有效量」或「治療有效量」在結合化合物使用時係指足以提供期望生物結果之化合物之量。該結果可為降低及/或減輕疾病之體徵、症狀或病因或生物系統之任何其他期望變化。舉例而言，對於治療用途而言，「有效量」係使疾病在臨床上顯著減輕所需要之包含本文所揭示化合物之組合物的量。任一個別情形下之適當「有效量」可由熟習此項技術者使用常規實驗來測定。因此，表達「有效量」通常係指活性物質具有治療效應之量。在本情形下，活性物質係發炎體之抑制劑。 如本文所用之術語「治療(treat或treatment)」與術語「預防」同義且欲指示疾病發生之延緩、預防疾病發生及/或減輕將發生或預計發生之該等症狀之嚴重程度。因此，該等術語包括改善現有疾病症狀、預防額外症狀、改善或預防症狀之潛在病因、抑制病症或疾病，例如阻滯病症或疾病之發生、減輕病症或疾病、使病症或疾病消退、減輕由疾病或病症引起之病況、或終止或減輕疾病或病症之症狀。 除非另外指示，否則本揭示內容中所用之術語「病症」意指術語疾病、病況或病且可與其互換使用。 藉由使用術語「醫藥上可接受之」或「藥理上可接受之」意欲意指並非生物學上或其他方面不期望之物質 - 該材料可投與個體而不引起任何實質上不期望之生物學效應或以有害方式與包含其之組合物之任何組分相互作用。 本揭示內容之中所用之術語「載劑」涵蓋載劑、賦形劑及稀釋劑，且意指參與將醫藥藥劑自個體之身體之一個器官或部分攜載或傳輸至身體之另一器官或部分的材料、組合物或媒劑，例如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封材料。賦形劑應基於期望劑型之相容性及釋放曲線性質進行選擇。實例性載劑材料包括(例如)黏合劑、懸浮劑、崩解劑、填充劑、表面活性劑、增溶劑、穩定劑、潤滑劑、潤濕劑、稀釋劑、噴霧乾燥分散液及諸如此類。 術語「醫藥上相容之載劑材料」可包含(例如)阿拉伯樹膠、明膠、膠體二氧化矽、甘油磷酸鈣、乳酸鈣、麥芽糊精、甘油、矽酸鎂、酪蛋白酸鈉、大豆卵磷脂、氯化鈉、磷酸三鈣、磷酸二鉀、乳酸硬脂酸鈉、卡拉膠、甘油單酯、甘油二酯、預明膠化澱粉及諸如此類。參見(例如) Hoover, John E.,Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975。 如本文所用術語「個體」涵蓋哺乳動物及非哺乳動物。哺乳動物之實例包括但不限於任何哺乳動物綱成員：人類；非人靈長類動物，例如黑猩猩及其他猿及猴類；農業動物，例如牛、馬、綿羊、山羊、豬；家畜，例如兔、狗及貓；實驗室動物，包括齧齒類動物，例如大鼠、小鼠及天竺鼠及諸如此類。非哺乳動物之實例包括(但不限於)鳥、魚及諸如此類。在本發明之一個實施例中，哺乳動物係人類。 本發明亦包括化合物之「前藥」。術語「前藥」意指可藉由代謝方式(例如，藉由水解)在活體內轉化成所揭示之化合物或活性成分的化合物。前藥可藉由熟習此項技術者已知之技術製備。該等技術通常修飾給定化合物中之適當官能基，例如羥基、胺基、羧基等基團。然而，該等經修飾之官能基藉由常規操縱或在活體內再生成初始官能基。前藥之實例包括(但不限於)酯(例如，乙酸酯、甲酸酯及苯甲酸酯衍生物)、本發明化合物中羥基或胺基官能基之胺基甲酸酯(例如，N,N-二甲基胺基羰基)、醯胺(例如，三氟乙醯基胺基、乙醯基胺基及諸如此類)及諸如此類。由於已知前藥會增強醫藥之諸多期望品質(例如可溶性、生物利用度、製造、運輸、藥效動力學等)，故可以前藥形式遞送本發明化合物。例如，即使在母體藥物不可生物利用時，前藥亦可藉由經口投與供生物利用。因此，本發明意欲涵蓋本文所主張化合物之前藥、其遞送方法及含有其之組合物。一般而言，前藥係在投與後轉化或代謝成生理活性物質之藥物本身的衍生物。轉化可為自發的，例如生理環境中之水解，或可為酶催化的。前藥包括可經氧化、還原、胺化、去胺化、羥基化、去羥基化、水解、酯化、烷基化、去烷基化、醯化、去醯化、磷酸化及/或區磷酸化以產生活性化合物之化合物。 如本文所用之術語「IC50 」係指將可量測之活性、表型或反應(例如諸如腫瘤細胞等細胞之生長或增殖)抑制50%的濃度。IC50 值可自適當劑量-反應曲線例如藉由眼或藉由使用適當曲線擬合或統計軟體來估計。更準確地，IC50 值可使用非線性回歸分析來測定。 如本揭示內容中所用之術語「投與(administered、administration或administering)係指直接向個體投與所揭示之化合物或所揭示之化合物之醫藥上可接受之鹽或組合物，或向個體投與該化合物或該化合物之醫藥上可接受之鹽或組合物的前藥衍生物或類似物，其可藉由使需要治療之個體與該化合物接觸或以其他方式將該個體暴露於該化合物而在該個體之身體(包括動物)內形成等效量之活性化合物。 如本文所用之「烷基」意指具有1至10個碳原子之直鏈或具支鏈飽和鏈。代表性飽和烷基包括(但不限於)甲基、乙基、正丙基、異丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基及諸如此類，以及較長烷基，例如庚基及辛基及諸如此類。烷基可未經取代或經取代。含有3個或更多個碳原子之烷基可為直鏈或具支鏈的。如本文所用之「低碳烷基」意指具有1至6個碳原子之烷基。 如本文所用之「烯基」包括含有2至12個碳原子之無支鏈或具支鏈烴鏈。「烯基」含有至少一個雙鍵。烯基之雙鍵可未經偶聯或偶聯至另一不飽和基團。烯基之實例包括(但不限於)乙基烯基、乙烯基、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基、4-(2-甲基-3-丁烯)-戊烯基及諸如此類。烯基可未經取代或經取代。如本文定義之烯基亦可為具支鏈或直鏈的。 如本文所用之「炔基」包括含有2至12個碳原子之無支鏈或具支鏈不飽和烴鏈。「炔基」含有至少一個三鍵。炔基之三鍵可未經偶聯或偶聯至另一不飽和基團。炔基之實例包括(但不限於)乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基、4-甲基-1-丁炔基、4-丙基-2-戊炔基、4-丁基-2-己炔基及諸如此類。炔基可未經取代或經取代。 術語「羥基(hydroxyl或hydroxy)」意指OH基團； 如本文所用之術語「烷氧基」係指在鏈中含有1至12個碳原子且含有末端「O」之直鏈或具支鏈飽和烴，亦即-O(烷基)。烷氧基之實例包括(但不限於)甲氧基、乙氧基、丙氧基、丁氧基、第三丁氧基或戊氧基。 亦應注意，假定本文之文字說明、方案、實例及表格中之任何具有不飽和化合價之碳原子以及雜原子具有足夠氫原子數目以使化合價達到飽和。 如本文所用，在提及氫時亦可指氘取代(若期望)。如本文所用之術語「氘」意指具有奇數個質子及中子之氫之穩定同位素。 術語「鹵基」或「鹵素」係指氟、氯、溴或碘。 如本文所用之術語「鹵代烷基」係指如本文定義之烷基，其經一或多個鹵素取代。鹵代烷基之實例包括(但不限於)三氟甲基、二氟甲基、五氟乙基、三氯甲基等。 如本文所用之術語「鹵代烷氧基」係指如本文定義之烷氧基，其經一或多個鹵素取代。鹵代烷基之實例包括(但不限於)三氟甲氧基、二氟甲氧基、五氟乙氧基、三氯甲氧基等。 如本文所用之術語「氰基」意指藉由三鍵碳原子接合至氮原子之取代基，亦即。 如本文所用之術語「胺基」意指含有至少一個氮原子之取代基。具體而言，NH2 、-NH(烷基)或烷基胺基、-N(烷基)2 或二烷基胺基、醯胺、甲醯胺、脲及磺醯胺取代基包括於術語「胺基」中。 除非另外明確定義，否則術語「芳基」係指具有1至3個芳香族環之環狀芳香族烴基團，包括單環或二環基團，例如苯基、聯苯或萘基。若含有兩個芳香族環(二環等)，則芳基之芳香族環可在單一點接合(例如，聯苯)或稠合(例如，萘基)。芳基可視情況在任何附接點由一或多個取代基(例如1至5個取代基)取代。取代基自身可視情況經取代。此外，在含有兩個稠合環時，本文中定義之芳基可具有與完全飽和環稠合之不飽和或部分飽和環。該等芳基之實例性環系統包括(但不限於)苯基、聯苯、萘基、蒽基、酚萘烯基(phenalenyl)、菲基、二氫茚基、茚基、四氫萘基、四氫苯并輪烯基(tetrahydrobenzoannulenyl)及諸如此類。 除非另有明確定義，否則「雜芳基」意指5至18個環原子之單價單環或多環芳香族基團或含有一或多個選自N、O或S之環雜原子之多環芳香族基團，其餘環原子係C。如本文定義之雜芳基亦意指二環雜芳香族基團，其中雜原子選自N、O或S。芳香族基團視情況獨立地經一或多個本文所述之取代基取代。取代基自身可視情況經取代。實例包括(但不限於)苯并噻吩、呋喃基、噻吩基、吡咯基、吡啶基、吡嗪基、吡唑基、嗒嗪基、嘧啶基、咪唑基、異噁唑基、噁唑基、噁二唑基、吡嗪基、吲哚基、噻吩-2-基、喹啉基、苯并吡喃基、異噻唑基、噻唑基、噻二唑基、噻吩并[3,2-b]噻吩、三唑基、三嗪基、咪唑并[1,2-b]吡唑基、呋喃并[2,3-c]吡啶基、咪唑并[1,2-a]吡啶基、吲唑基、吡咯并[2,3-c]吡啶基、吡咯并[3,2-c]吡啶基、吡唑并[3,4-c]吡啶基、苯并咪唑基、噻吩并[3,2-c]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[2,3-b]吡啶基、苯并噻唑基、吲哚基、吲哚啉基、吲哚啉酮基、二氫苯并噻吩基、二氫苯并呋喃基、苯并呋喃、烷基、硫烷基、四氫喹啉基、二氫苯并噻嗪、二氫苯并氧雜環己基、喹啉基、異喹啉基、1,6-萘啶基、苯并[de]異喹啉基、吡啶并[4,3-b][1,6]萘啶基、噻吩并[2,3-b]吡嗪基、喹唑啉基、四唑并[1,5-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、異吲哚基、吡咯并[2,3-b]吡啶基、吡咯并[3,4-b]吡啶基、吡咯并[3,2-b]吡啶基、咪唑并[5,4-b]吡啶基、吡咯并[1,2-a]嘧啶基、四氫吡咯并[1,2-a]嘧啶基、3,4-二氫-2H-1λ2 -吡咯并[2,1-b]嘧啶、二苯并[b,d]噻吩、吡啶-2-酮、呋喃并[3,2-c]吡啶基、呋喃并[2,3-c]吡啶基、1H-吡啶并[3,4-b][1,4]噻嗪基、苯并噁唑基、苯并異噁唑基、呋喃并[2,3-b]吡啶基、苯并噻吩基、1,5-萘啶基、呋喃并[3,2-b]吡啶、[1,2,4]三唑并[1,5-a]吡啶基、苯并[1,2,3]三唑基、咪唑并[1,2-a]嘧啶基、[1,2,4]三唑并[4,3-b]嗒嗪基、苯并[c][1,2,5]噻二唑基、苯并[c][1,2,5]噁二唑、1,3-二氫-2H-苯并[d]咪唑-2-酮、3,4-二氫-2H-吡唑并[1,5-b][1,2]噁嗪基、4,5,6,7-四氫吡唑并[1,5-a]吡啶基、噻唑并[5,4-d]噻唑基、咪唑并[2,1-b][1,3,4]噻二唑基、噻吩并[2,3-b]吡咯基、3H-吲哚基及其衍生物。此外，在含有兩個稠合環時，本文中定義之雜芳基可具有與完全飽和環稠合之不飽和或部分飽和環。 如本文所用術語「環烷基」係指每個環具有3至18個碳原子之飽和或部分飽和、單環、稠合或螺多環碳環。環烷基環或碳環可視情況在任何附接點由一或多個取代基(例如1至5個取代基)取代。取代基自身可視情況經取代。環烷基之實例包括(但不限於)環丙基、環丁基、環戊基、環己基、環庚基、環辛基、降冰片烷基、降冰片烯基、二環[2.2.2]辛基、二環[2.2.2]辛烯基、十氫萘基、八氫-1H-茚基、環戊烯基、環己烯基、環己-1,4-二烯基、環己-1,3-二烯基、1,2,3,4-四氫萘基、八氫戊烯基、3a,4,5,6,7,7a-六氫-1H-茚基、1,2,3,3a-四氫戊烯基、二環[3.1.0]己基、二環[2.1.0]戊基、螺[3.3]庚基、二環[2.2.1]庚基、二環[2.2.1]庚-2-烯基、二環[2.2.2]辛基、6-甲基二環[3.1.1]庚基、2,6,6-三甲基二環[3.1.1]庚基及其衍生物。 如本文所用術語「環烯基」係指每個環具有3至18個碳原子之部分飽和、單環、稠合或螺多環碳環且含有至少一個雙鍵。環烯基可視情況在任何附接點由一或多個取代基(例如1至5個取代基)取代。取代基自身可視情況經取代。 如本文所用術語「雜環烷基」或「雜環基」係指4至18個原子之飽和或部分不飽和及非芳香族單環或稠合或螺、多環狀環結構，該等原子含有碳及取自氧、氮或硫之雜原子，且其中環碳或雜原子間無共用之非定域π-電子(芳香性)。雜環烷基或雜環基環結構可由一或多個取代基取代。取代基自身可視情況經取代。雜環烷基或雜環基環之實例包括(但不限於)氧雜環丁基、氮雜環丁基、四氫呋喃基、吡咯啶基、噁唑啉基、噁唑啶基、噻唑啉基、噻唑啶基、吡喃基、噻喃基、四氫吡喃基、二氧戊環基(dioxalinyl)、六氫吡啶基、嗎啉基、硫嗎啉基、硫嗎啉基S-氧化物、硫嗎啉基S-二氧化物、六氫吡嗪基、氮呯基、氧雜環庚三烯基(oxepinyl)、二氮呯基、托烷基(tropanyl)、高托烷基、二氫噻吩-2(3H)-酮基、四氫噻吩1,1-二氧化物、2,5-二氫-1H-吡咯基、咪唑啶-2-酮、吡咯啶-2-酮、二氫呋喃-2(3H)-酮、1,3-二氧戊環-2-酮、異噻唑啶1,1-二氧化物、4,5-二氫-1H-咪唑基、4,5-二氫噁唑基、環氧乙基、吡唑啶基、4H-1,4-噻嗪基、硫嗎啉基、1,2,3,4-四氫吡啶基、1,2,3,4-四氫吡嗪基、1,3-噁嗪烷-2-酮、四氫-2H-噻喃1,1-二氧化物、7-氧雜二環[2.2.1]庚基、1,2-硫氮雜環庚烷1,1-二氧化物、八氫-2H-喹嗪基、1,3-二氮雜二環[2.2.2]辛基、2,3-二氫苯并[b][1,4]二氧雜環己烯、3-氮雜二環[3.2.1]辛基、8-氮雜螺[4.5]癸烷、8-氧雜-3-氮雜二環[3.2.1]辛基、2-氮雜二環[2.2.1]庚烷、2,8-二氮雜螺[5.5]十一烷基、2-氮雜螺[5.5]十一烷基、3-氮雜螺[5.5]十一烷基、十氫異喹啉基、1-氧雜-8-氮雜螺[4.5]癸基、8-氮雜二環[3.2.1]辛基、1,4'-聯六氫吡啶基、氮雜環庚烷基、8-氧雜-3-氮雜二環[3.2.1]辛基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、5,6,7,8-四氫咪唑并[1,2-a]吡啶基、1,4-二氮雜環庚烷基、吩噁噻基、苯并[d][1,3]二氧雜環戊烯基、2,3-二氫苯并呋喃基、2,3-二氫苯并[b][1,4]二氧雜環己烯基、4-(六氫吡啶-4-基)嗎啉基、3-氮雜螺[5.5]十一烷基、十氫喹啉基、六氫吡嗪-2-酮、1-(吡咯啶-2-基甲基)吡咯啶基、1,3'-聯吡咯啶基及6,7,8,9-四氫-1H,5H-吡唑并[1,2-a][1,2]二氮呯基。 如本文所用之數值範圍意欲包括連續整數。舉例而言，表示為「0至5」之範圍將包括0、1、2、3、4及5。 如本文所用術語「經取代」意指指定基團或部分帶有一或多個適宜取代基，其中取代基可在一或多個位置連接至指定基團或部分。舉例而言，經環烷基取代之芳基可指示，環烷基利用鍵或藉由與芳基稠合且共用兩個或更多個共同原子而連接至芳基之一個原子。 如本文所用術語「未經取代」意指指定基團不帶有取代基。 術語「視情況經取代」應理解為意指給定化學部分(例如，烷基)可(但無需)鍵結至其他取代基(例如，雜原子)。例如，視情況經取代之烷基可為完全飽和烷基鏈(即，純烴)。或者，相同視情況經取代之烷基可具有不同於氫之取代基。例如，其可沿著鏈在任一點結合至鹵素原子、羥基或本文所述之任何其他取代基。因此，術語「視情況經取代」意指給定化學部分具有含有其他官能基之潛能，但並不一定具有任何其他官能基。用於所述基團之可選取代中之適宜取代基包括(但不限於)側氧基、-鹵素、C1 -C6 烷基、C1 -C6 烷氧基、C1 -C6 鹵代烷基、C1 -C6 鹵代烷氧基、-OC1 -C6 烯基、-OC1 -C6 炔基、-C1 -C6 烯基、-C1 -C6 炔基、-OH、CN (氰基)、-CH2 CN、-OP(O)(OH)2 、-C(O)OH、-OC(O)C1 -C6 烷基、-C(O)C1 -C6 烷基、-C(O)-C0 -C6 烷基烯基-環烷基、-C(O)-C0 -C6 烷基烯基-雜環烷基、-C(O)-C0 -C6 烷基烯基-芳基、-C(O)-C0 -C6 烷基烯基-雜芳基、-OC(O)OC1 -C6 烷基、NH2 、NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、-C(O)NH2 、-C(O)NH(C1 -C6 烷基)、-C(O)N(C1 -C6 烷基)2 、-C(O)NH環烷基、-C(O)N(C1 -C6 烷基)環烷基、-C(O)NH雜環烷基、-C(O)N(C1 -C6 烷基)雜環烷基、-C(O)NH芳基、-C(O)N(C1 -C6 烷基)芳基、-C(O)NH雜芳基、-C(O)N(C1 -C6 烷基)雜芳基、-S(O)2 -C1 -C6 烷基、-S(O)2 -C1 -C6 鹵代烷基、-S(O)2 -環烷基、-S(O)2 -雜環烷基、-S(O)2 -芳基、-S(O)2 -雜芳基-C0 -C6 烷基烯基-S(O)2 NH2 、-S(O)2 NHC1 -C6 烷基、-S(O)2 N(C1 -C6 烷基)2 、-S(O)2 NH環烷基、-S(O)2 NH雜環烷基、-S(O)2 NH芳基、-S(O)2 NH雜芳基、-NHS(O)2 C1 -C6 烷基、-N(C1 -C6 烷基)S(O)2 (C1 -C6 烷基)、-NHS(O)2 芳基、-N(C1 -C6 烷基)S(O)2 芳基、-NHS(O)2 雜芳基、-N(C1 -C6 烷基)S(O)2 雜芳基、-NHS(O)2 環烷基、-N(C1 -C6 烷基)S(O)2 環烷基、-NHS(O)2 雜環烷基、-N(C1 -C6 烷基)S(O)2 雜環烷基、-N(C1 -C6 烷基)S(O)2 芳基、-C0 -C6 烷基烯基-芳基、-C0 -C6 烷基烯基-雜芳基、-C0 -C6 烷基烯基-環烷基、-C0 -C6 烷基烯基-雜環烷基、-O-芳基、-NH-芳基及N(C1 -C6 烷基)芳基。取代基自身可視情況經取代。在顯示多官能部分時，與核之附接點係由線指示，例如，(環烷基氧基)烷基-係指烷基係與核之附接點，而環烷基經由氧基附接至烷基。「視情況經取代」亦係指「經取代」或「未經取代」，具有上述含義。 如本文所用之術語「氧雜」係指「-O-」基團。 如本文所用之術語「側氧基」係指「=O」基團。 術語「溶劑合物」係指由溶質及溶劑形成之可變化學計量之複合物。出於本發明之目的，該等溶劑可不干擾溶質之生物活性。適宜溶劑之實例包括(但不限於)水、甲醇、乙醇及乙酸。其中水係溶劑分子之溶劑合物通常稱作水合物。水合物包括含有化學計算量之水之組合物、以及含有可變量之水之組合物。 如本文所採用之術語「鹽」表示利用無機及/或有機酸形成之酸性鹽、以及利用無機及/或有機鹼形成之鹼性鹽。另外，在該式化合物含有鹼性部分(例如但不限於吡啶或咪唑)及酸性部分(例如但不限於羧酸)二者時，可形成兩性離子(「內鹽」)且其包括於如本文所用之術語「鹽」內。醫藥上可接受之(即，無毒之生理上可接受之)鹽較佳，但其他鹽亦可用。例如，可藉由使該式化合物與一定量(例如1當量)之酸或鹼在諸如可沈澱鹽之介質等介質中或在水性介質中反應、隨後凍乾來形成式化合物之鹽。 在本發明之另一實施例中，式(I)化合物係鏡像異構物。在一些實施例中，該等化合物係(S )-鏡像異構物。在其他實施例中，該等化合物係(R )-鏡像異構物。在其他實施例中，式(I)化合物可為(+)或(-)鏡像異構物。 應瞭解，本發明內包括所有異構形式，包括其混合物。若化合物含有雙鍵，則取代基可為E或Z構形。若化合物含有經二取代之環烷基，則環烷基取代基可具有順式或反式構形。本發明亦欲包括所有互變異構物形式。 各種式之化合物及其鹽、溶劑合物、酯及前藥可以其互變異構形式(例如作為醯胺或亞胺基醚)存在。本文涵蓋所有該等互變異構形式作為本發明之一部分。 各種式之化合物可含有不對稱或手性中心，且因此以不同立體異構形式存在。各種式之化合物之所有立體異構形式以及其混合物(包括外消旋混合物)形成本發明之一部分。另外，本發明包涵所有幾何及位置異構物。舉例而言，若各種式之化合物納入雙鍵或稠合環，則順式-及反式-形式二者以及混合物涵蓋於本發明之範疇內。本文揭示之每一化合物包括符合化合物之一般結構之所有鏡像異構物。化合物可呈外消旋或鏡像異構純形式或立體化學方面之任何其他形式。分析結果可反映針對外消旋形式、鏡像異構純形式或立體化學方面之任何其他形式所收集之數據。 非鏡像異構物混合物可基於其物理化學差異藉由彼等熟習此項技術者熟知之方法(例如藉由層析及/或分段結晶)分離成其個別非鏡像異構物。鏡像異構物可藉由以下方式進行分離：藉由與適當光學活性化合物(例如，手性助劑，例如手性醇或Mosher醯氯)反應而將鏡像異構物混合物轉化成非鏡像異構物混合物，分離該等非鏡像異構物並將個別非鏡像異構物轉化(例如，水解)成相應的純鏡像異構物。同樣，各種式之一些化合物可為阻轉異構物(例如經取代之二芳基)且被視為本發明之一部分。亦可藉由使用手性HPLC管柱分離鏡像異構物。 式(I)化合物亦可以不同互變異構形式存在，且所有該等形式皆包涵於本發明之範疇內。例如，化合物之所有酮-烯醇及亞胺-烯胺形式亦包括於本發明中。 本發明化合物(包括該等化合物之彼等鹽、溶劑合物、酯及前藥以及該等前藥之鹽、溶劑合物及酯)之所有立體異構物(例如，幾何異構物、光學異構物及諸如此類)，例如因各取代基上不對稱碳原子而存在之彼等，包括鏡像異構形式(其在即使不含不對稱碳時亦可存在)、旋轉異構形式、阻轉異構物及非鏡像異構形式，皆涵蓋於本發明範疇內，位置異構物(例如，4-吡啶基及3-吡啶基)亦涵蓋於本發明範疇內。(舉例而言，若各種式之化合物納入雙鍵或稠合環，則順式-及反式-形式二者以及混合物包涵於本發明之範疇內。例如，化合物之所有酮-烯醇及亞胺-烯胺形式亦包括於本發明中。)本發明化合物之個別立體異構物可(例如)實質上不含其他異構物，或可為(例如)外消旋物之混合物，或可與所有其他立體異構物或其他所選立體異構物混合。本發明之手性中心可具有S或R構形，如由IUPAC 1974 Recommendations所定義。 本發明亦包涵本發明之同位素標記化合物，除一或多個原子由原子質量或質量數不同於自然界中通常所發現的原子質量或質量數的原子置換外，其與本文所述彼等相同。可納入本發明化合物中之同位素的實例包括氫、碳、氮、氧、磷、氟及氯之同位素，例如分別為2 H (或D)、3 H、13 C、14 C、15 N、18 O、17 O、31 P、32 P、35 S、18 F及36 Cl。 某些同位素標記之各種式之化合物(例如經3 H及14 C標記之彼等)可用於化合物及/或受質組織分佈分析中。氚化(亦即3 H)及碳-14 (亦即14 C)同位素因其易於製備及可檢測性而尤佳。此外，用諸如氘(亦即2 H)等較重同位素進行取代因具有更強之代謝穩定性從而可提供某些治療優點(例如活體內半衰期延長或劑量需要減少)，且因此可在一些情況下較佳。同位素標記之各種式之化合物通常可藉由類似於方案中及/或下文實例中所揭示之彼等之以下程序、藉由用適當同位素標記之試劑取代未經同位素標記之試劑來製備。 在一些實施例中，化合物包含至少一個氘原子。舉例而言，本發明化合物中一或多個氫原子可由氘置換或取代。在一些實施例中，化合物包含兩個或更多個氘原子。在一些實施例中，化合物包含1、2、3、4、5、6、7、8、9、10、11或12個氘原子。 式(I)化合物可形成亦在本發明範疇內之鹽。應瞭解，除非另有說明，否則本文提及該式化合物包括提及其鹽。 本發明係關於如本文所述之化合物及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物，以及包含一或多種如本文所述之化合物或其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物的醫藥組合物。 在本發明中，提及式(1b)包括提及式(1b)-1且對於式(Ic)、(Id)及(Ig)類似。在本發明中，提及(例如)式1b-1g包括提及式(1b)-1、(Ic)-1、(Id)-1、(1g)-1及(Ih)-1。化合物 本發明提供具有式(I)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。 本發明提供具有式(Ia)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。 本發明提供具有式(Ib)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。 在某些實施例中，本發明提供具有式(Ib)之結構之化合物，其具有式(Ib)-1：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群： 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。 本發明提供具有式(Ic)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。 在某些實施例中，本發明提供具有式(Ic)之結構之化合物，其具有式(Ic)-1：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群： 及； 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。 本發明提供具有式(Id)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。 在某些實施例中，本發明提供具有式(Id)之結構之化合物，其具有式(Id)-1：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、NH(C1 -C6 烷基)或N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。 本發明提供具有式(Ie)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。 本發明提供具有式(If)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。 本發明提供具有式(Ig)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。式(If)化合物在R1 取代基中不含鹼性胺基。式(1g)化合物內之磺醯脲部分使得該等化合物之pka值在5.2至6.2之範圍內，從而將其表徵為弱有機酸。此結構之化合物可展示低體積之活體內分佈且可展現高血漿蛋白結合。 在某些實施例中，本發明提供具有式(Ig)之結構之化合物，其具有式(Ig)-1：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：及， R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地選自H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 、-NS(O)2 R6 取代；或 兩個在同一個碳上之之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NS(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基。 本發明提供具有式(Ih)之結構之化合物，及其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物，其中X1 、R1 、R2 、R3 及R4 係如上文所述。式(Ih)化合物含有鹼性胺基。向式(1h)化合物(其亦帶有酸性磺醯脲部分)中納入鹼性胺基預計將以具有淨零電荷之兩性離子形式存在。兩性離子化合物可具有與弱有機酸不同之物理化學性質。顯著地，可存在增加體積之活體內分佈以及降低之血漿蛋白結合。 在某些實施例中，本發明提供具有式(Ih)之結構之化合物，其具有式(Ih)-1：及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：及， R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地選自H、-NHR6 、-NR6 R7 、C1 -C6 烷基及含N之雜環基；其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基。 在式I之某些實施例中，在R1 係、或時，則至少一個A2 係N、NR5 、O、S或S(O)2 。在式Ia-Id之某些實施例中，在R1 係或時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。 在本文所述之式之某些實施例中，X1 係O。在某些實施例中，X1 係S。在某些實施例中，X1 係。在某些實施例中，X1 係。 在本文所述之式之某些實施例中，R2 係。在式I之某些實施例中，R2 係。在式Ia-Id之某些實施例中，R2 係。在某些實施例中，R2 係。在某些實施例中，R2 係。 在本文所述式之某些實施例中，R2 係。 在式I之某些實施例中，R5 係H、D、鹵素、CN、-OR6 或C1 -C6 烷基。在某些實施例中，R5 係H、鹵素或C1 -C6 烷基。在某些實施例中，R5 係H、鹵素或甲基。在某些實施例中，R5 係H、氟、氯或甲基。在某些實施例中，R5 係H。在某些實施例中，R5 係鹵素。在某些實施例中，R5 係氟。在某些實施例中，R5 係氯。在某些實施例中，R5 係甲基。 在式Ia-Id之某些實施例中，R5b 係H、D、鹵素、CN、-OR6 或C1 -C6 烷基。在某些實施例中，R5b 係H、鹵素或C1 -C6 烷基。在某些實施例中，R5b 係H、鹵素或甲基。在某些實施例中，R5b 係H、氟、氯或甲基。在某些實施例中，R5b 係H。在某些實施例中，R5b 係鹵素。在某些實施例中，R5b 係氟。在某些實施例中，R5b 係氟。在某些實施例中，R5b 係甲基。 在式I之某些實施例中，R2 係。在式Ia-Id之某些實施例中，R2 係。在某些實施例中，n係0、1或2。 在式I之某些實施例中，每一R5 獨立地係H、鹵素、OH、CN、-NO2 、-OR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C3 -C8 環烷基。在某些實施例中，每一R5 獨立地選自由H、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN組成之群。 在式Ia-Id之某些實施例中，每一R5b 獨立地係H、鹵素、OH、CN、-NO2 、-OR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C3 -C8 環烷基。在某些實施例中，每一R5b 獨立地選自由H、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN組成之群。 在式I之某些實施例中，R2 係。在式Ia-Id之某些實施例中，R2 係。在式I之某些實施例中，R2 係。在式Ia-Id之某些實施例中，R2 係。 在本文所述之式之某些實施例中，R2 選自由以下組成之群：及。在某些實施例中，其中R2 選自由以下組成之群：及。在某些實施例中，R2 係。 在式Ie-Ih之某些實施例中，R2 係，其中R5b2 、R5b3 、R5b4 、R5b5 及R5b6 中之至少一者係C1 -C6 烷基或C3 -C8 環烷基，其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。在某些實施例中，R5b2 、R5b3 、R5b4 、R5b5 及R5b6 中之至少一者係C1 -C6 烷基或C3 -C8 環烷基，其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經鹵素取代。 在本文所述之式之某些實施例中，R1 係視情況經取代之C1 -C6 烷基。在某些實施例中，R1 係C1 -C6 烷基。在某些實施例中，R1 係C1 -C3 烷基。在某些實施例中，R1 係甲基。在某些實施例中，R1 係視情況經取代之C1 -C6 烯基。在某些實施例中，R1 係視情況經取代之C1 -C6 炔基。在某些實施例中，R1 係-(CH2 )m -O-(CH2 )m -CH3 ，每一m獨立地係1至4之整數。 在本文所述之式之某些實施例中，R1 係選自由以下組成之群：在本文所述之式之某些實施例中，R1 係。 在本文所述之式之某些實施例中，R1 係、或、 在本文所述之式之某些實施例中，R1 係,或。 在本文所述之式之某些實施例中，R1 係 或。 在本文所述之式之某些實施例中，R1 係,或。 在本文所述之式之某些實施例中，R1 係 或。 在本文所述之式之某些實施例中，R1 係。在某些實施例中，R1 係。在某些實施例中，R1 係。 在本文所述之式之某些實施例中，係包含A2 之環中之單鍵，藉此形成飽和環。在某些實施例中，1至2個係包含A2 之環中之雙鍵，藉此形成不飽和環。 在式I之某些實施例中，A係CR5 。在式Ia-Id之某些實施例中，A係CR5a 。在本文所述之式之某些實施例中，A係N。 在式I之某些實施例中，A1 係NR5 。在式Ia-Id之某些實施例中，A1 係NR5a 。在本文所述之式之某些實施例中，A1 係O。在本文所述之式之某些實施例中，A1 係S。在本文所述之式之某些實施例中，A1 係C(O)。 在本文所述之式之某些實施例中，每一A2 獨立地係CH2 或O。在某些實施例中，每一A2 係CH2 。 在式I之某些實施例中，一個A係CR5 且另一A係N。在某些實施例中，每一A2 獨立地係C(R5 )2 、NR5 或O。 在式Ia-Id之某些實施例中，一個A係CR5a 且另一A係N。在某些實施例中，每一A2 獨立地係C(R5a )2 、NR5a 或O。 在式I之某些實施例中，R5 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經取代。 在式Ia之某些實施例中，每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經取代。 在式Ia之某些實施例中，每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經取代。 在式I之某些實施例中，兩個R5 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子。在某些實施例中，C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經取代。 在式Ia-Id之某些實施例中，兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子。在某些實施例中，C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經取代。在某些實施例中，C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-NH2 、NH(C1 -C6 烷基)或N(C1 -C6 烷基)2 取代。在某些實施例中，兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基，其視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。 在本文所述之式之某些實施例中，兩個在同一個碳上之R5 可形成側氧基。在式Ia-Id之某些實施例中，兩個在同一個碳上之R5a 可形成側氧基。 在式Ib-Id之某些實施例中，每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OH、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。在某些實施例中，R5a 係C1 -C6 烷基，其視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、NH(C1 -C6 烷基)或N(C1 -C6 烷基)2 取代。在某些實施例中，R5a 係雜環基，其視情況經D、鹵素、C1 -C6 烷基、-OH、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。 在式Ib-Id之某些實施例中，兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。在某些實施例中，兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基，其視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。 在式Ib-Id之某些實施例中，兩個在同一個碳上之R5a 可形成側氧基。 在式Ib-Id之某些實施例中，每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。 在式I之某些實施例中，每一R5 獨立地係H、-NHR6 或-NR6 R7 。在某些實施例中，每一A2 獨立地係C(R5 )2 或O；且每一R5 獨立地係H、-NHR6 或-NR6 R7 。 在式Ia-Id之某些實施例中，每一R5a 獨立地係H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。在某些實施例中，每一A2 獨立地係C(R5a )2 或O；且每一R5a 獨立地係H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。 在本文所述之式之某些實施例中，R1 係選自由以下組成之群：及， 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代；且 R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地選自H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代。 在本文所述之式之某些實施例中，R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基，其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子。在某些實施例中，C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經取代。 在本文所述之式之某些實施例中，R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基。在某些實施例中，雜環基或雜芳基視情況經取代。 在式Ib-Id之某些實施例中，R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。在某些實施例中，R6 係C1 -C6 烷基，其視情況經D、鹵素、C1 -C6 烷基、-OH、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。在某些實施例中，R7 係C1 -C6 烷基，其視情況經D、鹵素、C1 -C6 烷基、-OH、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。 如上文式Ie中所述，R2 可為，其中每一Rb10 、Rb11 、Rb12 、Rb13 、Rb14 及Rb15 獨立地係H、-OH或側氧基。在某些實施例中，Rb10 、Rb11 、Rb12 、Rb13 、Rb14 及Rb15 中之一者係-OH或側氧基且其餘係H。在某些實施例中，Rb10 、Rb11 、Rb12 、Rb13 、Rb14 及Rb15 中之一者係-OH且其餘係H。在某些實施例中，Rb10 、Rb11 、Rb12 、Rb13 、Rb14 及Rb15 中之一者係側氧基且其餘係H。 如上文式Ie-Ih中所述，X1 係O或S。在式Ie-Ig之某些實施例中，X1 係O。在某些實施例中，X1 係S。 如上文式Ie-Ih中所述，R2 係或。 在式Ie-Ih之某些實施例中，R2 係。 如上文式Ie-Ih中所述，X2 係N或CR5b1 。在式Ie-Ih之某些實施例中，X2 係CR5b1 。在某些實施例中，X2 係N。 如上文式Ie-Ih中所述，R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。 在式Ie-Ih之某些實施例中，R5b1 係H、鹵素或C1 -C6 烷基。在某些實施例中，R5b1 係H、鹵素或甲基。在某些實施例中，R5b1 係H、氟、氯或甲基。在某些實施例中，R5b1 係H。在某些實施例中，R5b1 係鹵素。在某些實施例中，R5b1 係氟。在某些實施例中，R5b1 係氯。在某些實施例中，R5b1 係甲基。在式Ie-Ih之某些實施例中，R5b1 係視情況經取代之C1 -C6 烷基。在某些實施例中，R5b1 係視情況經鹵素取代之C1 -C6 烷基。在某些實施例中，R5b1 係-OR6 。在某些實施例中，R5b1 係-OH。 在式Ie-Ih之某些實施例中，R2 係。在某些實施例中，R2 係。 在式Ie-Ih之某些實施例中，R2 係。 如上文式Ie-Ih中所述，每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代。 在式Ie-Ih之某些實施例中，每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、CN、-NO2 、-OR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C3 -C8 環烷基。在某些實施例中，每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地選自由H、D、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN組成之群。在某些實施例中，R5b2 、R5b3 、R5b4 、R5b5 及R5b6 中之至少一者不為氫。在某些實施例中，R5b2 、R5b3 、R5b4 、R5b5 及R5b6 中之一者係-OR6 。在某些實施例中，R5b2 、R5b3 、R5b4 、R5b5 及R5b6 中之一者係-OH。 在式Ie-Ih之某些實施例中，R2 係。在式Ie-Ih之某些實施例中，R2 係。 在式Ie-Ih之某些實施例中，R2 選自由以下組成之群：及。在某些實施例中，其中R2 選自由以下組成之群：,及。在某些實施例中，R2 係。 在式Ie-Ih之某些實施例中，兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代。在某些實施例中，兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基或雜環基，其中C3 -C8 環烷基及雜環基視情況經鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代。 在式Ie-Ih之某些實施例中，R2 係。在某些實施例中，每一R5b2 及R5b4 選自由以下組成之群：H、D、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN。 在式Ie-Ih之某些實施例中，R2 係。 如上文式Ie-Ih中所述，R1 係選自由以下組成之群： 及，其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環。 在式Ie-Ih之某些實施例中，代表單鍵。在式Ie-Ih之某些實施例中，代表雙鍵。在某些實施例中，係包含A2 之環中之單鍵，藉此形成飽和環。 在式Ie-Ih之某些實施例中，R1 係或。在某些實施例中，R1 係或。 如上文式Ie-Ih中所述，每一A獨立地係CR5a1 或N；且每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 。 在式Ie-Ih之某些實施例中，一個A係CR5a1 且另一A係N。在某些實施例中，每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。 如上文式Ie-Ih中所述，每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代。 在式Ie-Ih之某些實施例中，每一R5a1 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基或雜環基，其中該等C1 -C6 烷基、C3 -C8 環烷基及雜環基視情況經鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代。 如上文式Ie-Ih中所述，每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； 在式Ie、If及Ig之某些實施例中，每一R5a2 獨立地係H、鹵素、OH、-OR6 、C1 -C6 烷基、C3 -C8 環烷基或雜環基；其中該等C1 -C6 烷基、C3 -C8 環烷基及雜環基視情況經鹵素、C1 -C6 烷基、-OR6 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代。 在式Ie、If及Ih之某些實施例中，每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基或雜環基；其中該等C1 -C6 烷基、C3 -C8 環烷基及雜環基視情況經鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代。 在式Ie、If及Ih之某些實施例中，每一R5a2 獨立地係H、-NHR6 或C1 -C6 烷基；其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代。在某些實施例中，每一R5a2 獨立地係H或含N之雜環基；其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代。 在式Ie、If之某些實施例中，每一A2 獨立地係C(R5a2 )2 或O；且每一R5a2 獨立地係H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基；其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、 -NR6 C(O)R6 或-NR6 S(O)2 R6 取代。 在式Ie-Ih之某些實施例中，兩個在同一個碳上之R5a2 可形成側氧基。 在式Ie-If之某些實施例中，R1 係選自由以下組成之群：及， 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地選自H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 可形成側氧基。 在式Ie-Ig之某些實施例中，R1 係選自由以下組成之群：及， 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 選自H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 可形成側氧基。 在式Ie-If及Ih之某些實施例中，R1 係選自由以下組成之群：及， 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、 - NR6 C(O)OR6 或-NR6 C(O)R6 取代；且 R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地選自H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基；其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代。 在本文所述之式之某些實施例中，R1 係。在某些實施例中，一個A係CR5a1 且另一A係N。在某些實施例中，每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。在某些實施例中，其中每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，其中兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述之式之某些實施例中，R1 係，其具有式，其中： A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ； A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、- NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 可形成側氧基。 在本文所述之式之某些實施例中，R1 係，其中 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； R5a2c 及R5a2d 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 可形成側氧基。 在某些實施例中，每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2c 及R5a2d 中之一者係H且另一者獨立地係鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述之式之某些實施例中，R1 係，其中 R5a2a 及R5a2b 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2a 及R5a2b 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2a 及R5a2b 可形成側氧基。 在某些實施例中，每一R5a2a 及R5a2b 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，每一R5a2a 及R5a2b 獨立地係H、鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2a 及R5a2b 中之一者係H且另一者獨立地係鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2a 及R5a2b 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述之式之某些實施例中，R1 係，其中 R5a2e 及R5a2f 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2e 及R5a2f 可形成側氧基。 在某些實施例中，每一R5a2e 及R5a2f 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，每一R5a2e 及R5a2f 獨立地係H、鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2e 及R5a2f 中之一者係H且另一者獨立地係鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述之式之某些實施例中，R1 係，其中 R5a2c 及R5a2d 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH( C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 可形成側氧基。 在某些實施例中，每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2c 及R5a2d 中之一者係H且另一者獨立地係鹵素、OH、-OR6 、-NHR6 或-NR6 R7 。在某些實施例中，R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述之式之某些實施例中，R1 係選自由以下組成之群： 及，其中係與化合物之其餘部分之連接。 在本文所述式中之某些實施例中，R1 係選自由以下組成之群：及，其中係與化合物之其餘部分之連接。 在本文所述之式之某些實施例中，R1 係選自由以下組成之群：及，其中係與化合物之其餘部分之連接。 在本文所述之式之某些實施例中，R1 係。在某些實施例中，一個A係CR5a1 且另一A係N。在某些實施例中，每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。在某些實施例中，其中每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，其中兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述之式之某些實施例中，R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ； A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； A2ij 係選自CR5a2 、C(R5a2i )(R5a2j )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 可形成側氧基。 在本文所述式之某些實施例中，R1 係。 在本文所述之式之某些實施例中，R1 係。在某些實施例中，一個A係CR5a1 且另一A係N。在某些實施例中，每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。在某些實施例中，其中每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，其中兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述式之某些實施例中，R1 係，其具有式，其中 A2ab 係選自C(R5a2a )(R5a2b )、NR5a2 、O、S或S(O)2 ； A2cd 係選自C(R5a2c )(R5a2d )、NR5a2 、O、S或S(O)2 ； A2ef 係選自C(R5a2e )(R5a2f )、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 可形成側氧基。 在本文所述式之某些實施例中，R1 係。 在本文所述式之某些實施例中，R1 係。在某些實施例中，一個A係CR5a1 且另一A係N。在某些實施例中，每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。在某些實施例中，其中每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。在某些實施例中，其中兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 在本文所述式之某些實施例中，R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ； A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代，或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代，或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 可形成側氧基。 本發明提供式Ie-If化合物，其中 X1 係O； R1 係選自由以下組成之群：及； 其中代表單鍵； 每一A2 獨立地係C(R5a2 )2 或O； X2 係CR5b1 ； 每一R5a1 獨立地係H或C1 -C6 烷基；其中該C1 -C6 烷基視情況經D、鹵素、-OR6 、-NH2 、NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基或雜環基；其中該等C1 -C6 烷基及雜環基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 或-S(O)2 -R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素或C1 -C6 烷基； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、-CN、-OR6 、C1 -C6 烷基或C3 -C8 環烷基；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基或雜芳基，其中C3 -C8 環烷基、雜環基或雜芳基視情況經鹵素或C1 -C6 烷基取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 炔基或芳基；其中該等C1 -C8 烷基、C2 -C8 炔基及芳基視情況經D、鹵素或C1 -C6 烷基取代。 在某些實施例中，化合物具有下式：。 在某些實施例中，化合物具有下式：。 在式(I)之某些實施例中，X1 係O且R2 係。 在式(I)之某些實施例中，X1 係O且R1 係。 在式(I)之某些實施例中，R1 係且R2 係。 在一些實施例中，本發明提供式(I)化合物，其具有一個、兩個或三個以下特徵： a) X係O； b) R1 係； c) R2 係； d) X2 係CH或CF。 在一些實施例中，本發明提供式(I)化合物，其具有一個、兩個或三個以下特徵： a) X係O； b) R1 係； c) R2 係； d) X2 係CH。 (I)在一些實施例中，本發明提供式(I)化合物，其具有一個、兩個或三個以下特徵： a) X係S； b) R1 係； c) R2 係； d) X2 係CH。 在一些實施例中，本發明提供式(I)化合物，其具有一個、兩個或三個以下特徵： a) X係O； b) R1 係甲基； c) R2 係； d) X2 係CH。 在一些實施例中，本發明提供式(I)化合物，其具有一個、兩個或三個以下特徵： a) X係S； b) R1 係甲基； c) R2 係； d) X2 係CH。 在一些實施例中，本發明提供式(I)化合物，其具有一個、兩個或三個以下特徵： a) X係O； b) R1 係； c) R2 係； d) X2 係CH。 在一些實施例中，本發明提供式Ie-If化合物，其具有一個、兩個或三個以下特徵： a) X係O； b) R1 係； c) R5a2c 及R5a2d 中之一者係H且另一者獨立地係鹵素、OH、-OR6 、-NHR6 或-NR6 R7 ； d) R2 係； e) X2 係CH或CF。 在一些實施例中，本發明提供式(I)化合物，其具有一個、兩個或三個以下特徵： a) X係O； b) R1 係； c) R2 係。 在某些實施例中，本發明提供， N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺及其醫藥上可接受之鹽。 在某些實施例中，本發明提供， N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)甲烷磺醯胺及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供及其醫藥上可接受之鹽。 在某些實施例中，本發明提供選自由以下組成之群之化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：在某些實施例中，本發明提供選自由以下組成之群之化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物： 。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物： 。在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物： 。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物： 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：。 在某些實施例中，本發明提供以下化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物：除非另有說明，否則本文所繪示之結構亦欲包括僅在一或多個同位素富集原子存在方面不同之化合物。舉例而言，具有本發明結構、只是由氘或氚置換氫原子、或由13 C或14 C置換碳原子、或由15 N置換氮原子、或用17 O或18 O置換氧原子之化合物在本發明範疇內。該等同位素標記之化合物可用作研究或診斷工具。治療方法 所揭示之化合物(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物)及其醫藥上可接受之鹽具有作為醫藥劑之活性，如本文所論述。 本發明提供治療或預防疾病、病症或病況之方法，其包括如下步驟：投與有效量之本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物為有此需要之個體治療或預防疾病、病症或病況。 本發明提供本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物或本發明醫藥組合物，其用於治療或預防有需要之個體之疾病、病症或病況。 本發明提供本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物之用途，其用於治療或預防有需要之個體之疾病、病症或病況。 本發明提供本發明化合物及其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物及互變異構物之用途，其用於製造用於治療或預防疾病、病症或病況之藥劑。 在某些實施例中，疾病、病症或病況係對發炎體之活化之抑制有反應者。在一個特定實施例中，疾病、病症或病況係對NLRP3發炎體之活化之抑制有反應者。 根據此實施例，本發明化合物或其醫藥上有效之鹽、溶劑合物或前藥係NLRP3之特異性抑制劑。 在另一實施例中，該疾病、病症或病況對IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞中之一或多者之調節有反應。在某些實施例中，該疾病、病症或病況對IL-1β及IL-18中之一或多者之調節有反應。 在一個實施例中，調節係抑制IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22及IL-33中之一或多者。在一個實施例中，調節係抑制IL-1β及IL-18中之一或多者。 在一個實施例中，Th17細胞之調節係藉由抑制IL-17之產生及/或分泌。 在一般實施例中，疾病、病症或病況係免疫系統、心血管系統、內分泌系統、胃腸道、腎系統、呼吸系統、中樞神經系統之疾病、病症或病況，係癌症或其他惡性病，及/或係由病原體引起或與其相關。 應瞭解，根據疾病、病症及病況之寬類別定義之該等一般實施例並不互斥。就此而言，可根據上述一般實施例中之一者以上對任何特定疾病、病症或病況進行分類。非限制性實例係I型糖尿病，其係自體免疫疾病及內分泌系統之疾病。 在一個實施例中，疾病、病症或病況係免疫系統之疾病、病症或病況。在特定實施例中，疾病、病症或病況係發炎性疾病、病症或病況或自體免疫疾病、病症或病況。 在一個實施例中，疾病、病症或病況係肝之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係肺之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係皮膚之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係心血管系統之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係癌症、腫瘤或其他惡性病。如本文所用之癌症腫瘤及惡性病係指疾病、病症或病況，或係指與該等疾病、病症或病況相關之細胞或組織，該等疾病、病症或病況之特徵在於失常或異常細胞增殖、分化及/或遷移且經常伴隨包括一或多個遺傳突變或與腫瘤形成、腫瘤標記之表現、抑瘤基因表現或活性之損失相關之其他遺傳變化之失常或異常分子表型及/或失常或異常細胞表面標記表現。在一般實施例中，癌症、腫瘤及惡性病可包括肉瘤、淋巴瘤、白血病、實體腫瘤、胚細胞瘤、神經膠質瘤、癌瘤、黑色素瘤及轉移癌症，但並不限於此。癌症腫瘤及惡性病之更廣泛清單可參見國家癌症研究院(National Cancer Institutes)網站http://www.cancer.gov/cancertopics/types/alphalist，其全文以引用方式併入本文中。 在一個實施例中，疾病、病症或病況係腎系統之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係胃腸道之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係呼吸系統之疾病、病症或病況。 在另一實施例中，疾病、病症或病況係內分泌系統之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係中樞神經系統(CNS)之疾病、病症或病況。 在一個實施例中，疾病、病症或病況係由病原體引起或與其相關。病原體可為病毒、細菌、原生生物、寄生蟲或真菌或能夠感染哺乳動物之任何其他生物體，但並不限於此。 病毒之非限制性實例包括流行性感冒病毒、巨細胞病毒、艾伯斯坦-巴爾病毒(Epstein Barr Virus)、人類免疫缺乏病毒(HIV)、α病毒(例如屈公病病毒(Chikungunya)及羅氏河病毒(Ross River virus))、黃病毒(例如登革熱病毒(Dengue virus)、茲卡病毒(Zika virus))及乳頭瘤病毒，但並不限於此。 病原體細菌之非限制性實例包括金黃色葡萄球菌(Staphylococcus aureus)、幽門螺旋桿菌(Helicobacter pylori)、炭疽芽孢桿菌(Bacillus anthracis)、百日咳博德特氏桿菌(Bordatella pertussis)、白喉棒狀桿菌(Corynebacterium diptheriae)、破傷風梭菌(Clostridium tetani)、肉毒梭菌(Clostridium botulinum)、肺炎鏈球菌、釀膿鏈球菌(Streptococcus pyogenes)、單核球增多性李氏菌(Listeria monocytogenes)、流行性感冒嗜血桿菌(Hemophilus influenzae)、多殺性巴斯德桿菌(Pasteureiia multicida)、痢疾志賀桿菌(Shigella dysenteriae)、結核分枝桿菌(Mycobacterium tuberculosis)、麻風分枝桿菌(Mycobacterium leprae)、肺炎支原體、支原體人型(Mycoplasma hominis)、腦膜炎雙球菌(Neisseria meningitidis)、淋病雙球菌(Neisseria gonorrhoeae)、立氏立克次體(Rickettsia rickettsii)、嗜肺軍團菌(Legionella pneumophila)、克雷伯氏肺炎菌(Klebsiella pneumoniae)、綠膿桿菌(Pseudomonas aeruginosa)、痤瘡丙酸桿菌(Propionibacterium acnes)、梅毒密螺旋體(Treponema pallidum)、沙眼披衣菌(Chlamydia trachomatis)、霍亂弧菌(Vibrio cholerae)、鼠傷寒沙門氏菌(Salmonella typhimurium)、傷寒沙門桿菌(Salmonella typhi)、伯氏疏螺旋體(Borrelia burgdorferi)及鼠疫耶爾辛氏菌(Yersinia pestis)，但並不限於此。 原生生物之非限制性實例包括瘧原蟲屬(Plasmodium)、巴貝蟲屬(Babesia)、梨形鞭毛蟲屬(Giardia)、阿米巴屬(Entamoeba)、利什曼原蟲屬(Leishmania)及錐蟲(Trypanosomes)，但並不限於此。 寄生蟲之非限制性實例包括蠕蟲，包括血吸蟲，蛔蟲、絛蟲及吸蟲，但並不限於此。 真菌之非限制性實例包括念珠菌屬(Candida)及麴菌屬(Aspergillus)，但並不限於此。 在特定實施例中，疾病、病症或病況選自由以下組成之群：組成型發炎，包括隱熱蛋白相關週期症候群(CAPS)：穆-韋二氏症候群(Muckle-Wells syndrome，MWS)、家族性冷因性自體發炎症候群(FCAS)及新生兒發作性多系統發炎性疾病(NOMID)；包括自體發炎性疾病：家族性地中海熱(FMF)、TNF受體相關之週期性症候群(TRAPS)、甲羥戊酸激酶缺乏症(MKD)、高免疫球蛋白血症D及週期性發熱症候群(H IDS)、介白素1受體拮抗劑缺乏(DIRA)、馬吉德症候群(Majeed syndrome)、化膿性關節炎、壞疽性膿皮症及痤瘡(PAPA)、A20之單一對偶基因不足性(HA20)、兒科肉芽腫關節炎(PGA)、PLCG2相關之抗體缺乏症及免疫失調(PLAID)、PLCG2相關之自體發炎、抗體缺乏及免疫失調(APLAID)、鐵粒幼細胞性貧血伴B細胞免疫缺乏、週期性發熱、發育遲緩(SIFD)；史維特氏症候群(Sweet s syndrome)、慢性非細菌性骨髓炎(CNO)、慢性復發性多病灶骨髓炎(CRMO)及滑膜炎、痤瘡、膿疱病、骨肥大、骨炎症候群(SAPHO)；自體免疫疾病，包括多發性硬化(MS)、1型糖尿病、牛皮癬、類風濕性關節炎、貝賽特氏病(Behcet's disease)、休格倫氏症候群(Sjogren's syndrome)及薛尼茲勒氏症候群(Schnitzler syndrome)；呼吸疾病，包括特發性肺纖維化(IPF)、慢性阻塞性肺病症(COPD)、類固醇抗性氣喘、石棉肺、矽肺及囊性纖維化；中樞神經系統疾病，包括帕金森氏病(Parkinson's disease)、阿茲海默氏病、運動神經元疾病、杭丁頓氏病(Huntington's disease)、腦型瘧疾及來自肺炎球菌腦膜炎之腦損傷；代謝疾病，包括2型糖尿病、動脈粥樣硬化、肥胖症、痛風、假性痛風；眼睛疾病，包括眼上皮之彼等、年齡相關性黃斑退化(AMD)、角膜感染、眼色素層炎及乾眼；腎病，包括慢性腎病、草酸鹽腎病變及糖尿病腎病變；肝病，包括非酒精性脂肪性肝炎及酒精性肝病；皮膚之發炎反應，包括接觸過敏及曬傷；關節之發炎反應，包括骨關節炎、全身性青少年型特發性關節炎、成人發作性史迪爾氏病(Still's disease)、復發性多發性軟骨炎；病毒感染，包括α病毒(屈公病病毒、羅氏河病毒)及黃病毒(登革熱病毒及茲卡病毒)、流行性感冒、HIV；化膿性汗腺炎(HS)及其他囊腫引起之皮膚病；癌症，包括肺癌轉移、胰臟癌、胃癌、脊髓發育不良症候群、白血病；多發性肌炎；中風；心肌梗塞；移植物抗宿主病；高血壓；結腸炎；蠕蟲感染；細菌感染；腹主動脈瘤；傷口癒合；抑鬱症、心理應激壓力；心包炎，包括卓斯勒症候群(Dressler's syndrome)、缺血性再灌注損傷、及經判定帶有NLRP3之生殖細胞系或體細胞非靜默突變之個體的任何疾病。 在所述之彼等之一個非限制性實例中，所治療之疾病、病症或病況係NASH。NLRP3發炎體活化對於NASH中之發炎性招募至關重要，且NLRP3之抑制既可預防亦可逆轉肝纖維化。本發明化合物藉由打斷NLRP3發炎體在肝組織中之功能可引起肝發炎之組織學減輕、巨噬細胞及嗜中性球之減少招募及NF-κΒ活化之抑制。NLRP3之抑制可減少促-IL-1β及正規化肝及循環IL-1β、IL-6及MCP-1含量之肝表現，藉此輔助治療疾病。 在所述之彼等之又一非限制性實例中，所治療之疾病、病症或病況係嚴重類固醇抗性(SSR)氣喘。呼吸道感染誘導肺中之NLRP3發炎體/半胱天冬酶-l/IL-Ιβ信號傳導軸，其促使SSR氣喘。NLRP3發炎體招募並活化促-半胱天冬酶-1以誘導IL-1β反應。因此，NLRP3發炎體誘導之IL- β反應在控制感染中係重要的，然而，過度活化引起失常發炎且與SSR氣喘及COPD之致病機制相關。靶向特定疾病過程之本發明化合物之投與比利用類固醇或IL-1β非特異性抑制發炎反應在治療上更具吸引力。因此，利用本發明化合物靶向NLRP3發炎體/半胱天冬酶-1/IL-1β信號傳導軸可用於治療SSR氣喘及其他類固醇抗性發炎病況。 在所述之彼等之又一非限制性實例中，所治療之疾病、病症或病況係帕金森氏病。帕金森氏病係最常見之神經退化運動障礙且特徵在於多巴胺神經元之選擇性損失，伴有錯摺疊之a-突觸核蛋白(Syn)累積至路易體(Lewy body)中。慢性小神經膠質神經發炎在該疾病中早期明顯，且經提出以驅動病狀。 在帕金森病之進展中假定小神經膠質NLRP3之重要作用。NLRP3發炎體係由原纖維Syn經由Syk激酶依賴性機制活化，且亦在不存在Syn病狀下在多巴胺變性之早期出現，且驅動神經元損失。本發明化合物可藉由原纖維Syn或粒線體功能障礙阻斷NLRP3發炎體活化且藉此賦予黑質紋狀體多巴胺系統之有效神經保護並輔助治療帕金森氏病。 在某些實施例中，該方法治療或預防疾病或病症，包括但不限於細菌感染、病毒感染、真菌感染、發炎性腸病、乳糜瀉、結腸炎、腸增生、癌症、代謝症候群、肥胖症、類風濕性關節炎、肝病、肝纖維化、肝臟脂肪變性、脂肪肝病、非酒精性脂肪肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)。 在某些實施例中，疾病、病症或病況選自由以下組成之群：NASH (非酒精性脂肪性肝炎)；CAPS (隱熱蛋白相關之週期性症候群)；IPF (特發性肺纖維化)；MI (R/I) (心肌梗塞及再灌注損傷)；痛風；I/O (免疫-腫瘤學)；氣喘；IBD (發炎性腸病)；腎纖維化；成人發作性史迪爾氏病；全身性青少年型特發性關節炎；腫瘤壞死因子受體相關之週期性症候群(TRAPS)；秋水仙鹼抗性家族性地中海熱(FMF)；超IgD症候群(HIDS)/甲羥戊酸激酶缺乏症(MKD)；創傷性腦損傷；帕金森氏病；中度至嚴重發炎性痤瘡；急性非以前之非感染性眼色素層炎(NIU)；AD (阿茲海默氏病)；COPD (慢性阻塞性肺病)；敗血症；MS (多發性硬化)；貝賽特氏病；RA (類風濕性關節炎)；侵蝕性骨關節炎；T1D (1型糖尿病)；T2D (2型糖尿病)；肥胖症；骨質疏鬆症；囊性纖維化；酒精性肝病；老化；HCC (肝細胞癌)；抑鬱症；子宮內膜異位症；壞疽性膿皮症(「PG」)、罕見潰瘍性皮膚病；狼瘡性腎炎；癲癇；缺血性中風；耳聾；鐮狀細胞疾病；SLE (全身性紅斑狼瘡)；及脊髓損傷。 對於上文提及之治療用途，當然，所投與劑量將隨著所用化合物、投與方式、期望治療及適應病症而變化。舉例而言，本發明化合物之日劑量(若吸入)可在約0.05微克/公斤體重(μg/kg)至約100微克/公斤體重(μg/kg)之範圍內。或者，若化合物係經口投與，則本發明化合物之日劑量可在約0.01微克/公斤體重(μg/kg)至約100毫克/公斤體重(mg/kg)之範圍內。醫藥組合物 所揭示之化合物(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物)及其醫藥上可接受之鹽可自身使用，但通常將以醫藥組合物形式投與，其中所揭示之化合物/鹽(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物及其鹽) (活性成分)與醫藥上可接受之佐劑、稀釋劑或載劑締合。用於選擇及製備適宜醫藥調配物之習用程序闡述於(例如) 「Pharmaceuticals - The Science of Dosage Form Designs」, M. E. Aulton, Churchill Livingstone, 1988中，其全文以引用方式併入本文中。 端視投與方式而定，醫藥組合物將包含約0.05 %w至約99 %w (重量百分比)、更特定而言約0.05 %w至約80 %w、仍更特定而言約0.10 %w至約70 %w且甚至更特定而言約0.10 %w至約50 %w之活性成分，所有重量百分比皆係基於總組合物。 本發明亦提供醫藥組合物，其包含如上文所定義之所揭示之化合物(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物)或其醫藥上可接受之鹽以及醫藥上可接受之佐劑、稀釋劑或載劑。 本發明進一步提供本發明醫藥組合物之製備方法，其包含混合如上文所定義之所揭示之化合物(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物)或其醫藥上可接受之鹽與醫藥上可接受之佐劑、稀釋劑或載劑。 醫藥組合物可以(例如)乳膏、溶液、懸浮液、七氟代烷(HFA)氣溶膠及乾燥粉末調配物(例如稱作Turbuhaler® 之吸入器裝置中之調配物)形式局部投與(例如投與至皮膚或肺及/或氣道)；或(例如)藉由以錠劑、膠囊、糖漿、粉末或顆粒形式經口投與全身性投與；或藉由以注射用無菌溶液、懸浮液或乳液形式非經腸投與(包括靜脈內、皮下、肌內、血管內或輸注)；或藉由以栓劑形式直腸投與。 本發明化合物(包括醫藥上可接受之鹽)之乾燥粉末調配物及加壓之HFA氣溶膠可藉由經口或經鼻吸入來投與。對於吸入而言，化合物期望地經細分。細分之化合物較佳具有小於10微米(μm)之質量中值直徑，且可借助於分散劑(例如C8 -C20 脂肪酸或其鹽(例如油酸)、膽汁鹽、磷脂、烷基醣、全氟化或聚乙氧基化表面活性劑或其他醫藥上可接受之分散劑)懸浮於推進劑混合物中。 本發明化合物亦可藉助乾燥粉末吸入器投與。吸入器可為單劑量或多劑量吸入器，且可為呼吸致動之乾燥粉末吸入器。 一種可能係將細分之本發明化合物與載劑物質(例如單醣、二醣或多醣、糖醇或另一多元醇)混合。適宜載劑係糖，例如乳糖、葡萄糖、棉子糖、松三糖、乳糖醇、麥芽糖醇、海藻糖、蔗糖、甘露醇；及澱粉。或者，細分之化合物可由另一物質塗佈。亦可將粉末混合物分配至硬明膠膠囊中，每一膠囊含有期望劑量之活性化合物。 另一可能係將細分之粉末處理成球形，其在吸入程序期間分解。可將此球形化粉末填充至多劑量吸入器(例如稱作Turbuhaler® 者，其中劑量單位計量隨後由患者吸入之期望劑量)之藥物儲存器中。利用此系統，將具有或無載劑物質之活性成分遞送至患者。 另一可能係將化合物在聚合物基質(例如羥丙基甲基纖維素(HPMC)或乙酸琥珀酸羥丙基甲基纖維素(HPMCAS))中處理成非晶形分散液。顧名思義，噴霧乾燥之分散液(SDD)係藉由將藥物及聚合物溶解於有機溶劑中、將所得溶液霧化成小滴並蒸發至乾燥固體粒子來獲得。SDD通常適於使用各種最終經口劑型，包括膠囊及錠劑。 對於經口投與而言，可將本發明化合物與以下佐劑或載劑混合：例如乳糖、蔗糖、山梨醇、甘露醇；澱粉，例如馬鈴薯澱粉、玉米澱粉或支鏈澱粉；纖維素衍生物；黏合劑，例如明膠或聚乙烯基吡咯啶酮；及/或潤滑劑，例如硬脂酸鎂、硬脂酸鈣、聚乙二醇、蠟、石蠟及諸如此類；且隨後壓製成錠劑。若需要包衣錠劑，則如上文所述製備之核可經可含有(例如)阿拉伯膠、明膠、滑石粉及二氧化鈦之濃縮之糖溶液包衣。或者，錠劑可經溶解於容易揮發之有機溶劑中之適宜聚合物包衣。 對於軟明膠膠囊之製備，可將本發明化合物與(例如)植物油或聚乙二醇混合。硬明膠膠囊可含有使用用於錠劑之上文提及之賦形劑的化合物之顆粒。亦可將本發明化合物之液體或半固體調配物填充至硬明膠膠囊中。 用於經口施加之液體製劑可呈糖漿或懸浮液(例如含有本發明化合物之溶液，其餘部分係糖以及乙醇、水、甘油及丙二醇之混合物)形式。視情況，該等液體製劑可含有著色劑、矯味劑、糖精及/或羧甲基纖維素作為增稠劑或彼等熟習此項技術者已知之其他賦形劑。組合療法 本發明化合物(亦即式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物及其醫藥上可接受之鹽)亦可結合用於治療上述病況之其他化合物投與。 因此，本發明進一步係關於組合療法，其中本發明化合物或包含本發明化合物之醫藥組合物或調配物係同時或依序或作為與另一治療劑或試劑之組合製劑投與，用於治療所列示病況中之一或多者。合成化合物之方法 本發明化合物可藉由各種方法(包括標準化學法)製得。一種適宜合成途徑繪示於下文提供之方案中。 本發明化合物(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物)或其醫藥上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物可藉由如部分中所述之有機合成技術中已知之方法藉由以下合成方案來製備。在下述方案中，應充分理解，若需要，根據一般原則或化學法採用敏感或反應基團之保護基團。根據有機合成之標準方法操縱保護基團(T. W. Greene及P. G. M. Wuts, 「Protective Groups in Organic Synthesis」，第3版，Wiley, New York 1999，其全文以引用方式併入本文中)。在化合物合成之方便階段使用對彼等熟習此項技術者顯而易見之方法移除該等基團。選擇過程以及反應條件及其執行次序應與所揭示之化合物(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物)之製備一致。 彼等熟習此項技術者將識別式(I)化合物中是否存在立體中心。因此，本發明包括兩種可能之立體異構物(除非合成法中有指定)，且不僅包括外消旋化合物且亦包括個別鏡像異構物及/或非鏡像異構物。當希望化合物呈單一鏡像異構物或非鏡像異構物形式時，其可藉由立體特異性合成法或藉由拆分最終產物或任一合宜中間體來獲得。可藉由業內已知之任一適宜方法拆分最終產物、中間體或起始材料。參見(例如) 「Stereochemistry of Organic Compounds」，E. L. Eliel、S. H. Wilen及L. N. Mander (Wiley-Interscience, 1994)，其全文以引用方式併入本文中。 本文所述化合物可自市售起始材料製得或使用已知有機、無機及/或酶方法合成。化合物之製備 本發明化合物可依彼等熟習有機合成技術者熟知之多種方式來製備。舉例而言，可使用下述方法以及合成有機化學領域已知之合成方法或熟習此項技術者所瞭解的該等方法之變化形式來合成本發明化合物。例示性方法包括(但不限於)下文所述彼等方法。本發明化合物可藉由依循方案1中概述之步驟來合成。起始材料有市售或係藉由所報導文獻中已知之程序或如所例示來製得。 式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih可根據方案1中概述之一般程序製備。在方法A中，所揭示之化合物(例如，式I、Ia、Ib、Ic、Id、Ie、If、Ig及Ih化合物)易於自異氰酸磺醯基酯或異硫氰酸磺醯基酯(化合物A-1)與胺(化合物A-2)之反應獲得。在某些實施例中，在適當溶劑中用鹼處理化合物A-2。隨後，添加化合物A-1至化合物A-2中。該反應係在適宜溶劑(例如，四氫呋喃或二氯甲烷)中，於室溫至回流溫度下進行。 繼續參照方案1，在方法B中，很容易自異氰酸酯或異硫氰酸酯(化合物B-1)與磺醯胺(化合物B-2)之反應中獲得式(I)化合物。在某些實施例中，在適當溶劑中用鹼處理化合物B-2。隨後，添加化合物B-1至化合物B-2中。該反應係在適宜溶劑(例如，四氫呋喃或二氯甲烷)中，於室溫至回流溫度下進行。方案 1 實例性實施例 實施例I-1. 一種式I化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 及； 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5 或N； A1 係NR5 、O、S或C(O)； 每一A2 獨立地係CR5 、C(R5 )2 、N、NR5 、O、S或S(O)2 ； R2 係或； X2 係N或CR5 ； R3 及R4 係H； 每一R5 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；或 兩個R5 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；或 兩個在同一個碳上之R5 可形成側氧基； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5 、O、S或S(O)2 。 實施例I-2. 如實施例I-1之化合物，其中X1 係O。 實施例I-3. 如實施例I-1之化合物，其中X1 係S。 實施例I-4. 如實施例I-1至I-3中任一實施例之化合物，其中R2 係。 實施例I-5. 如實施例I-1至I-3中任一實施例之化合物，其中R2 係。 實施例I-6. 如實施例I-1至I-5中任一實施例之化合物，其中該等係包含A2 之環中之單鍵，藉此形成飽和環。 實施例I-7. 如實施例I-1至I-5中任一實施例之化合物，其中R1 係。 實施例I-8. 如實施例I-7之化合物，其中每一A2 獨立地係CH2 或O。 實施例I-9. 如實施例I-1至I-5中任一實施例之化合物，其中R1 係。 實施例I-10. 如實施例I-1至I-5中任一實施例之化合物，其中R1 係甲基。 實施例I-11. 如實施例I-1至I-9中任一實施例之化合物，其中該化合物具有下式：。 實施例I-12. 如實施例I-1之化合物，其係， N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺。 實施例I-13. 如實施例I-1之化合物，其係， N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)甲烷磺醯胺。 實施例I-14. 如實施例I-1之化合物，其選自由以下組成之群： 。 實施例I-15. 一種醫藥組合物，其包含如實施例I-1至I-14中任一實施例之化合物及醫藥上可接受之載劑。 實施例I-16. 一種治療或預防疾病、病症或病況之方法，其包括以下步驟：投與有效量之如實施例I-1至I-14中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，以藉此治療或預防該疾病、病症或病況。 實施例I-17. 如實施例I-16之方法，其中該疾病、病症或病況對發炎體之抑制有反應。 實施例I-18. 如實施例I-16或I-17之方法，其中該疾病、病症或病況係對NLRP3發炎體之活化之抑制有反應者。 實施例I-19. 如實施例I-16或I-17之方法，其中該疾病、病症或病況對IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞中之一或多者之調節有反應。 實施例I-20. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係免疫系統之疾病、病症或病況。 實施例I-21. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係發炎性疾病、病症或病況或自體免疫疾病、病症或病況。 實施例I-22. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係肝之疾病、病症或病況。 實施例I-23. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係肺之疾病、病症或病況。 實施例I-24. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係皮膚之疾病、病症或病況。 實施例I-25. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係心血管系統之疾病、病症或病況。 實施例I-26. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係癌症、腫瘤或其他惡性病。 實施例I-27. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係腎系統之疾病、病症或病況。 實施例I-28. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係胃腸道之疾病、病症或病況。 實施例I-29. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係呼吸系統之疾病、病症或病況。 實施例I-30. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係內分泌系統之疾病、病症或病況。 實施例I-31. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況係中樞神經系統(CNS)之疾病、病症或病況。 實施例I-32. 如實施例I-16至I-19中任一實施例之方法，其中該疾病、病症或病況選自由以下組成之群：組成型發炎、隱熱蛋白相關週期症候群(CAPS)、穆-韋二氏症候群(MWS)、家族性冷因性自體發炎症候群(FCAS)、新生兒發作性多系統發炎性疾病(NOMID)、自體發炎性疾病、家族性地中海熱(FMF)、TNF受體相關之週期性症候群(TRAPS)、甲羥戊酸激酶缺乏症(MKD)、高免疫球蛋白血症D、週期性發熱症候群(HIDS)、介白素1受體拮抗劑缺乏(DIRA)、馬吉德症候群、化膿性關節炎、壞疽性膿皮症及痤瘡(PAPA)、A20之單一對偶基因不足性(HA20)、兒科肉芽腫關節炎(PGA)、PLCG2相關之抗體缺乏症及免疫失調(PLAID)、PLCG2相關之自體發炎、抗體缺乏及免疫失調(APLAID)、鐵粒幼細胞性貧血伴B細胞免疫缺乏、週期性發熱、發育遲緩(SIFD)、史維特氏症候群、慢性非細菌性骨髓炎(CNO)、慢性復發性多病灶骨髓炎(CRMO)及滑膜炎、痤瘡、膿疱病、骨肥大、骨炎症候群(SAPHO)、自體免疫疾病(包括多發性硬化(MS)、1型糖尿病、牛皮癬、類風濕性關節炎、貝賽特氏病、休格倫氏症候群、薛尼茲勒氏症候群)、呼吸疾病、特發性肺纖維化(IPF)、慢性阻塞性肺病症(COPD)、類固醇抗性氣喘、石棉肺、矽肺、囊性纖維化、中樞神經系統疾病、帕金森氏病、阿茲海默氏病、運動神經元疾病、杭丁頓氏病、腦型瘧疾、來自肺炎球菌腦膜炎之腦損傷、代謝疾病、2型糖尿病、動脈粥樣硬化、肥胖症、痛風、假性痛風、眼睛疾病、眼上皮疾病、年齡相關性黃斑退化(AMD)、角膜感染、眼色素層炎、乾眼、腎病、慢性腎病、草酸鹽腎病變、糖尿病腎病變、肝病、非酒精性脂肪性肝炎、酒精性肝病、皮膚之發炎反應、接觸過敏、曬傷、關節之發炎反應、骨關節炎、全身性青少年型特發性關節炎、成人發作性史迪爾氏病、復發性多發性軟骨炎、病毒感染、α病毒感染、屈公病病毒感染、羅氏河病毒感染、黃病毒感染、登革熱病毒感染、茲卡病毒感染、流行性感冒、HIV感染、化膿性汗腺炎(HS)、囊腫引起之皮膚病、癌症、肺癌轉移、胰臟癌、胃癌、脊髓發育不良症候群、白血病、多發性肌炎、中風、心肌梗塞、移植物抗宿主病、高血壓、結腸炎、蠕蟲感染、細菌感染、腹主動脈瘤、傷口癒合、抑鬱症、心理應激壓力、心包炎、卓斯勒症候群、缺血性再灌注損傷、及經判定帶有NLRP3之生殖細胞系或體細胞非靜默突變之個體的任何疾病。 實施例I-33. 如實施例I-15之方法，其中該病症選自由以下組成之群：細菌感染、病毒感染、真菌感染、發炎性腸病、乳糜瀉、結腸炎、腸增生、癌症、代謝症候群、肥胖症、類風濕性關節炎、肝病、肝臟脂肪變性、脂肪肝病、肝纖維化、非酒精性脂肪肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)。 實施例I-34. 如實施例I-33之方法，其中該病症係非酒精性脂肪性肝炎(NASH)。 實施例I-35. 如實施例I-16至I-34中任一實施例之方法，其中該疾病、病症或病況之該治療或預防係對哺乳動物實施。 實施例I-36. 如實施例I-35之方法，其中該哺乳動物係人類個體。 實施例I-37. 一種調節生物靶標之活性之方法，其包含將該生物靶標暴露於如實施例I-1至I-14中任一實施例之化合物或其醫藥上有效之鹽、溶劑合物或前藥的步驟。 實施例I-38. 如實施例I-37之方法，其中該生物靶標可選自由以下組成之群：NLRP3發炎體、IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞。 實施例I-39. 一種如實施例I-1至I-14中任一實施例之化合物之用途，其用於治療對發炎體之抑制有反應的疾病、病症或病況。 實施例I-40. 如實施例I-1至I-14中任一實施例之化合物，其用於製造用於治療對發炎體之抑制有反應之疾病、病症或病況的藥劑。 實施例II-1. 一種式Ia化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；或 兩個R5b 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。實施例II-2. 一種式Ib化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。實施例II-3. 一種式Ic化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 烯基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係； X2 係N或CR5b ； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。實施例II-4. 一種式Id化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O、S、或； R1 係選自由以下組成之群：視情況經取代之C1 -C6 烷基、視情況經取代之C1 -C6 炔基、-(CH2 )m -O-(CH2 )m -CH3 、 其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a 或N； A1 係NR5a 、O、S或C(O)； 每一A2 獨立地係CR5a 、C(R5a )2 、N、NR5a 、O、S或S(O)2 ； R2 係； R3 及R4 係H； 每一R5a 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5a 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個在同一個碳上之R5a 可形成側氧基； 每一R5b 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-S(O)2 N(R6 )2 -、-S(O)2 R6 、-C(O)R6 、-C(O)OR6 、-C(O)NR6 R7 、-NR6 S(O)2 R7 、-S(O)R6 、-S(O)NR6 R7 、-NR6 S(O)R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基及C2 -C6 炔基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C8 炔基、C3 -C8 環烷基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C6 烷基、C2 -C8 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基及雜芳基視情況經D、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 每一m獨立地係1至4之整數；且 n係0至5之整數； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a 、O、S或S(O)2 。實施例II-5. 如實施例II-1至II-4中任一實施例之化合物，其中R1 係選自由以下組成之群： 實施例II-6. 如實施例II-1至II-5中任一實施例之化合物，其中X1 係O。 實施例II-7. 如實施例II-1至II-5中任一實施例之化合物，其中X1 係S。 實施例II-8. 如實施例II-1至II-3及II-5至II-7中任一實施例之化合物，其中R2 係。 實施例II-9. 如實施例II-1至II-3及II-5至II-7中任一實施例之化合物，其中R2 係。 實施例II-10. 如實施例II-1至II-9中任一實施例之化合物，其中該等包含A2 之環中之單鍵，藉此形成飽和環。 實施例II-11. 如實施例II-1至II-10中任一實施例之化合物，其中R1 係。 實施例II-12. 如實施例II-11之化合物，其中每一A2 獨立地係CH2 或O。 實施例II-13. 如實施例II-1至II-10中任一實施例之化合物，其中R1 係。 實施例II-14. 如實施例I-1至II-10中任一實施例之化合物，其中R1 係。 實施例II-15. 如實施例II-1至II-10中任一實施例之化合物，其中R1 係。 實施例II-16. 如實施例II-1至II-15中任一實施例之化合物，其中R1 係甲基。 實施例II-17. 如實施例II-1至II-3及II-5至II-16中任一實施例之化合物，其中該化合物具有下式：。 實施例II-18. 如實施例II-1之化合物，其係， N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺或其醫藥上可接受之鹽。 實施例II-19. 如實施例II-1之化合物，其係， N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)甲烷磺醯胺或其醫藥上可接受之鹽。 實施例II-20. 如實施例II-1之化合物，其係， 或其醫藥上可接受之鹽。 實施例II-21. 如請求項II-1之化合物，其係：， 或其醫藥上可接受之鹽。 實施例II-22. 如實施例II-1之化合物，其選自由以下組成之群：實施例II-23. 如實施例II-1之化合物，其選自由以下組成之群： 。 實施例II-24. 如實施例II-1至II-4中任一實施例之化合物，其選自由以下組成之群： 實施例II-25. 一種醫藥組合物，其包含如實施例II-1至II-24中任一實施例之化合物及醫藥上可接受之載劑。 實施例II-26. 一種治療或預防疾病、病症或病況之方法，其包括以下步驟：投與有效量之如實施例II-1至II-24中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，以藉此治療或預防該疾病、病症或病況。 實施例II-27. 如實施例II-25之方法，其中該疾病、病症或病況對發炎體之抑制有反應。 實施例II-28. 如實施例II-26或II-27之方法，其中該疾病、病症或病況係對NLRP3發炎體之活化之抑制有反應者。 實施例II-29. 如實施例II-26或II-27之方法，其中該疾病、病症或病況對IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞中之一或多者之調節有反應。 實施例II-30. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係免疫系統之疾病、病症或病況。 實施例II-31. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係發炎性疾病、病症或病況或自體免疫疾病、病症或病況。 實施例II-32. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係肝之疾病、病症或病況。 實施例II-33. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係肺之疾病、病症或病況。 實施例II-34. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係皮膚之疾病、病症或病況。 實施例II-35. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係心血管系統之疾病、病症或病況。 實施例II-36. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係癌症、腫瘤或其他惡性病。 實施例II-37. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係腎系統之疾病、病症或病況。 實施例II-38. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係胃腸道之疾病、病症或病況。 實施例II-39. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係呼吸系統之疾病、病症或病況。 實施例II-40. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係內分泌系統之疾病、病症或病況。 實施例II-41. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況係中樞神經系統(CNS)之疾病、病症或病況。 實施例II-42. 如實施例II-26至II-29中任一實施例之方法，其中該疾病、病症或病況選自由以下組成之群：組成型發炎、隱熱蛋白相關週期症候群(CAPS)、穆-韋二氏症候群(MWS)、家族性冷因性自體發炎症候群(FCAS)、新生兒發作性多系統發炎性疾病(NOMID)、自體發炎性疾病、家族性地中海熱(FMF)、TNF受體相關之週期性症候群(TRAPS)、甲羥戊酸激酶缺乏症(MKD)、高免疫球蛋白血症D、週期性發熱症候群(HIDS)、介白素1受體拮抗劑缺乏(DIRA)、馬吉德症候群、化膿性關節炎、壞疽性膿皮症及痤瘡(PAPA)、A20之單一對偶基因不足性(HA20)、兒科肉芽腫關節炎(PGA)、PLCG2相關之抗體缺乏症及免疫失調(PLAID)、PLCG2相關之自體發炎、抗體缺乏及免疫失調(APLAID)、鐵粒幼細胞性貧血伴B細胞免疫缺乏、週期性發熱、發育遲緩(SIFD)、史維特氏症候群、慢性非細菌性骨髓炎(CNO)、慢性復發性多病灶骨髓炎(CRMO)及滑膜炎、痤瘡、膿疱病、骨肥大、骨炎症候群(SAPHO)、自體免疫疾病(包括多發性硬化(MS)、1型糖尿病、牛皮癬、類風濕性關節炎、貝賽特氏病、休格倫氏症候群、薛尼茲勒氏症候群)、呼吸疾病、特發性肺纖維化(IPF)、慢性阻塞性肺病症(COPD)、類固醇抗性氣喘、石棉肺、矽肺、囊性纖維化、中樞神經系統疾病、帕金森氏病、阿茲海默氏病、運動神經元疾病、杭丁頓氏病、腦型瘧疾、來自肺炎球菌腦膜炎之腦損傷、代謝疾病、2型糖尿病、動脈粥樣硬化、肥胖症、痛風、假性痛風、眼睛疾病、眼上皮疾病、年齡相關性黃斑退化(AMD)、角膜感染、眼色素層炎、乾眼、腎病、慢性腎病、草酸鹽腎病變、糖尿病腎病變、肝病、非酒精性脂肪性肝炎、酒精性肝病、皮膚之發炎反應、接觸過敏、曬傷、關節之發炎反應、骨關節炎、全身性青少年型特發性關節炎、成人發作性史迪爾氏病、復發性多發性軟骨炎、病毒感染、α病毒感染、屈公病病毒感染、羅氏河病毒感染、黃病毒感染、登革熱病毒感染、茲卡病毒感染、流行性感冒、HIV感染、化膿性汗腺炎(HS)、囊腫引起之皮膚病、癌症、肺癌轉移、胰臟癌、胃癌、脊髓發育不良症候群、白血病、多發性肌炎、中風、心肌梗塞、移植物抗宿主病、高血壓、結腸炎、蠕蟲感染、細菌感染、腹主動脈瘤、傷口癒合、抑鬱症、心理應激壓力、心包炎、卓斯勒症候群、缺血性再灌注損傷、及經判定帶有NLRP3之生殖細胞系或體細胞非靜默突變之個體的任何疾病。 實施例II-43. 如實施例II-26之方法，其中該病症選自由以下組成之群：細菌感染、病毒感染、真菌感染、發炎性腸病、乳糜瀉、結腸炎、腸增生、癌症、代謝症候群、肥胖症、類風濕性關節炎、肝病、肝臟脂肪變性、脂肪肝病、肝纖維化、非酒精性脂肪肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)。 實施例II-44. 如實施例II-43之方法，其中該病症係非酒精性脂肪性肝炎(NASH)。 實施例II-45. 如實施例II-26至II-44中任一實施例之方法，其中該疾病、病症或病況之該治療或預防係對哺乳動物實施。 實施例II-46. 如實施例II-45之方法，其中該哺乳動物係人類個體。 實施例II-47. 一種調節生物靶標之活性之方法，其包含將該生物靶標暴露於如實施例II-1至II-24中任一實施例之化合物或其醫藥上有效之鹽、溶劑合物或前藥的步驟。 實施例II-48. 如實施例II-47之方法，其中該生物靶標可選自由以下組成之群：NLRP3發炎體、IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞。 實施例II-49. 一種如實施例II-1至II-24中任一實施例之化合物之用途，其用於治療對發炎體之抑制有反應的疾病、病症或病況。 實施例II-50. 如實施例II-1至II-24中任一實施例之化合物，其用於製造用於治療對發炎體之抑制有反應之疾病、病症或病況的藥劑。 實施例III-1. 一種式If化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。實施例III-2. 如實施例III-1之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中： X1 係O； R1 係選自由以下組成之群： 及； 其中代表單鍵； 每一A2 獨立地係C(R5a2 )2 或O； X2 係CR5b1 ； 每一R5a1 獨立地係H或C1 -C6 烷基；其中該C1 -C6 烷基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基或雜環基；其中該等C1 -C6 烷基及雜環基視情況經D、鹵素、-OR6 、-NH2 、NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 或-S(O)2 -R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素或C1 -C6 烷基； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、-CN、-OR6 、C1 -C6 烷基或C3 -C8 環烷基；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基或雜芳基，其中C3 -C8 環烷基、雜環基或雜芳基視情況經鹵素或C1 -C6 烷基取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 炔基或芳基；其中該等C1 -C8 烷基、C2 -C8 炔基及芳基視情況經D、鹵素或C1 -C6 烷基取代。 實施例III-3. 一種式Ig化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、 -NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。實施例III-4. 一種式Ih化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、-OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1-C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 其中至少一個R5a2 係-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。 實施例III-5. 一種式Ie化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； 每一Rb10 、Rb11 、Rb12 、Rb13 、Rb14 及Rb15 獨立地係H、-OH或側氧基； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。實施例III-6. 如實施例III-1及III-3至III-5中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中X1 係O。 實施例III-7. 如實施例III-1至III-6中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-8. 如實施例III-7之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中X2 係CR5b1 。 實施例III-9. 如實施例III-8之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5b1 係H、鹵素或C1 -C6 烷基。 實施例III-10. 如實施例III-8之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5b1 係H、氟、氯或甲基。 實施例III-11. 如實施例III-1至III-10中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-12. 如實施例III-1至III-10中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-13. 如實施例III-1至III-6中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-14. 如實施例III-13之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、CN、-NO2 、-OR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C3 -C8 環烷基。 實施例III-15. 如實施例III-1至III-13中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-16. 如實施例III-15之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地選自由H、D、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN組成之群。 實施例III-17. 如實施例III-1至III-16中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 選自由以下組成之群： 及。 實施例III-18. 如實施例III-1至III-17中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 選自由以下組成之群：及。 實施例III-19. 如實施例III-1至III-18中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-20. 如實施例III-1至III-13中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-21. 如實施例III-20之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5b2 及R5b4 選自由以下組成之群：H、D、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN。 實施例III-22. 如實施例III-20及III-21中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。 實施例III-23. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係或。 實施例III-24. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係或。 實施例III-25. 如實施例III-1至III-24中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。 實施例III-26. 如實施例III-1至III-25中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。 實施例III-27. 如實施例III-26之化合物，其中每一R5a2 獨立地係H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代。 實施例III-28. 如實施例III-27之化合物，其中R1 係選自由以下組成之群：及， 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代；且 R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地選自H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代。 實施例III-29. 如實施例III-1至III-23中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。 實施例III-30. 如實施例III-29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。 實施例III-31. 如實施例III-29至III-30中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。 實施例III-32. 如實施例III-29至III-30中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。 實施例III-33. 如實施例III-20至III-32中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 實施例III-34. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ；且 A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 可形成側氧基。 實施例III-35. 如實施例III-34之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； R5a2c 及R5a2d 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH( C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 可形成側氧基。 實施例III-36. 如實施例III-35之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。 實施例III-37. 如實施例III-35至III-36中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 實施例III-38. 如實施例III-34之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 R5a2a 及R5a2b 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2a 及R5a2b 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2a 及R5a2b 可形成側氧基。 實施例III-39. 如實施例III-38之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2a 及R5a2b 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。 實施例III-40. 如實施例III-38至III-39中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2a 及R5a2b 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 實施例III-41. 如實施例III-33之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 R5a2e 及R5a2f 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2e 及R5a2f 可形成側氧基。 實施例III-42. 如實施例III-41之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2e 及R5a2f 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。 實施例III-43. 如實施例III-41至III-42中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 實施例III-44. 如實施例III-34之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 R5a2c 及R5a2d 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH( C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 可形成側氧基。 實施例III-45. 如實施例III-44之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。 實施例III-46. 如實施例III-44至III-45中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。 實施例III-47. 如實施例III-29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係選自由以下組成之群： 實施例III-48. 如實施例III-29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係選自由以下組成之群：及。 實施例III-49. 如實施例III-29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係選自由以下組成之群：及。 實施例III-50. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。 實施例III-51. 如實施例III-50之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。 實施例III-52. 如實施例III-50至III-51中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。 實施例III-53. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ；且 A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； A2ij 係選自CR5a2 、C(R5a2i )(R5a2j )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 可形成側氧基。 實施例III-54. 如實施例III-50之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。 實施例III-55. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。 實施例III-56. 如實施例III-55之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。 實施例III-57. 如實施例III-55至III-56中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。 實施例III-58. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自C(R5a2a )(R5a2b )、NR5a2 、O、S或S(O)2 ； A2cd 係選自C(R5a2c )(R5a2d )、NR5a2 、O、S或S(O)2 ； A2ef 係選自C(R5a2e )(R5a2f )、NR5a2 、O、S或S(O)2 ；且 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 可形成側氧基。 實施例III-59. 如實施例III-55之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。 實施例III-60. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。 實施例III-61. 如實施例III-60之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。 實施例III-62. 如實施例III-60至III-61中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。 實施例III-63. 如實施例III-1至III-22中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ；且 A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代，或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代，或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 可形成側氧基。 實施例III-64. 如實施例III-1至III-63中任一實施例之化合物或其醫藥上可接受之鹽, 前藥, 溶劑合物, 水合物, 異構物或互變異構物，其中該等係包含A2 之環中之單鍵，藉此形成飽和環。 實施例III-65. 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其選自由以下組成之群： 。 實施例III-66. 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其選自由以下組成之群： 。 實施例III-67. 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其選自由以下組成之群：實施例III-68. 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其選自由以下組成之群： 。實施例III-69. 一種醫藥組合物，其包含如實施例III-1至III-68中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物以及醫藥上可接受之載劑。 實施例III-70. 一種治療或預防對發炎體之抑制有反應之疾病、病症或病況的方法，其包含投與有效量之如實施例III-1至III-68中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，為有此需要之個體治療或預防該疾病、病症或病況。 實施例III-71. 如實施例III-70之方法，其中該疾病、病症或病況係對NLRP3發炎體之活化之抑制有反應者。 實施例III-72. 如實施例III-70或III-71之方法，其中該疾病、病症或病況對IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞中之一或多者之調節有反應。 實施例III-73. 如實施例III-70或III-71之方法，其中該疾病、病症或病況對IL-1β及IL-18中之一或多者之調節有反應。 實施例III-74. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係免疫系統之疾病、病症或病況。 實施例III-75. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係發炎性疾病、病症或病況或自體免疫疾病、病症或病況。 實施例III-76. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係肝之疾病、病症或病況。 實施例III-77. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係肺之疾病、病症或病況。 實施例III-78. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係皮膚之疾病、病症或病況。 實施例III-79. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係心血管系統之疾病、病症或病況。 實施例III-80. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係癌症、腫瘤或其他惡性病。 實施例III-81. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係腎系統之疾病、病症或病況。 實施例III-82. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係胃腸道之疾病、病症或病況。 實施例III-83. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係呼吸系統之疾病、病症或病況。 實施例III-84. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係內分泌系統之疾病、病症或病況。 實施例III-85. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況係中樞神經系統(CNS)之疾病、病症或病況。 實施例III-86. 如實施例III-70至III-73中任一實施例之方法，其中該疾病、病症或病況選自由以下組成之群：組成型發炎、隱熱蛋白相關週期症候群(CAPS)、穆-韋二氏症候群(MWS)、家族性冷因性自體發炎症候群(FCAS)、新生兒發作性多系統發炎性疾病(NOMID)、自體發炎性疾病、家族性地中海熱(FMF)、TNF受體相關之週期性症候群(TRAPS)、甲羥戊酸激酶缺乏症(MKD)、高免疫球蛋白血症D、週期性發熱症候群(HIDS)、介白素1受體拮抗劑缺乏(DIRA)、馬吉德症候群、化膿性關節炎、壞疽性膿皮症及痤瘡(PAPA)、A20之單一對偶基因不足性(HA20)、兒科肉芽腫關節炎(PGA)、PLCG2相關之抗體缺乏症及免疫失調(PLAID)、PLCG2相關之自體發炎、抗體缺乏及免疫失調(APLAID)、鐵粒幼細胞性貧血伴B細胞免疫缺乏、週期性發熱、發育遲緩(SIFD)、史維特氏症候群、慢性非細菌性骨髓炎(CNO)、慢性復發性多病灶骨髓炎(CRMO)及滑膜炎、痤瘡、膿疱病、骨肥大、骨炎症候群(SAPHO)、自體免疫疾病(包括多發性硬化(MS)、1型糖尿病、牛皮癬、類風濕性關節炎、貝賽特氏病、休格倫氏症候群、薛尼茲勒氏症候群)、呼吸疾病、特發性肺纖維化(IPF)、慢性阻塞性肺病症(COPD)、類固醇抗性氣喘、石棉肺、矽肺、囊性纖維化、中樞神經系統疾病、帕金森氏病、阿茲海默氏病、運動神經元疾病、杭丁頓氏病、腦型瘧疾、來自肺炎球菌腦膜炎之腦損傷、代謝疾病、2型糖尿病、動脈粥樣硬化、肥胖症、痛風、假性痛風、眼睛疾病、眼上皮疾病、年齡相關性黃斑退化(AMD)、角膜感染、眼色素層炎、乾眼、腎病、慢性腎病、草酸鹽腎病變、糖尿病腎病變、肝病、非酒精性脂肪性肝炎、酒精性肝病、皮膚之發炎反應、接觸過敏、曬傷、關節之發炎反應、骨關節炎、全身性青少年型特發性關節炎、成人發作性史迪爾氏病、復發性多發性軟骨炎、病毒感染、α病毒感染、屈公病病毒感染、羅氏河病毒感染、黃病毒感染、登革熱病毒感染、茲卡病毒感染、流行性感冒、HIV感染、化膿性汗腺炎(HS)、囊腫引起之皮膚病、癌症、肺癌轉移、胰臟癌、胃癌、脊髓發育不良症候群、白血病、多發性肌炎、中風、心肌梗塞、移植物抗宿主病、高血壓、結腸炎、蠕蟲感染、細菌感染、腹主動脈瘤、傷口癒合、抑鬱症、心理應激壓力、心包炎、卓斯勒症候群、缺血性再灌注損傷、及經判定帶有NLRP3之生殖細胞系或體細胞非靜默突變之個體的任何疾病。 實施例III-87. 如實施例III-86之方法，其中該病症選自由以下組成之群：細菌感染、病毒感染、真菌感染、發炎性腸病、乳糜瀉、結腸炎、腸增生、癌症、代謝症候群、肥胖症、類風濕性關節炎、肝病、肝臟脂肪變性、脂肪肝病、肝纖維化、非酒精性脂肪肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)。 實施例III-88. 如實施例III-87之方法，其中該病症係非酒精性脂肪性肝炎(NASH)。 實施例III-89. 如實施例III-70至III-88中任一實施例之方法，其中該疾病、病症或病況之該治療或預防係對哺乳動物實施。 實施例III-90. 如實施例III-89之方法，其中該哺乳動物係人類個體。 實施例III-91. 一種調節生物靶標之活性之方法，其包含將該生物靶標暴露於如實施例III-1至III-68中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、異構物或互變異構物的步驟。 實施例III-92. 如實施例III-91之方法，其中該生物靶標可選自由以下組成之群：NLRP3發炎體、IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞。 實施例III-93. 如實施例III-91之方法，其中該生物靶標可選自由以下組成之群：IL-1β及IL-18。 實施例III-94. 一種抑制發炎體之活化之方法，其包含將生物靶標暴露於如實施例III-1至III-68中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物的步驟。 實施例III-95. 如實施例III-94之方法，其中該發炎體係NLRP3發炎體。 實施例III-96. 如實施例III-94或III-95之方法，其中發炎體之抑制與IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞中之一或多者相關。 實施例III-97. 如實施例III-96之方法，其中發炎體之抑制與IL-1β及IL-18中之一或多者相關。 實施例III-98. 一種如實施例III-1至III-68中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物的用途，其用於治療對發炎體之抑制有反應之疾病、病症或病況。 實施例III-99. 一種如實施例III-1至III-68中任一實施例之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其用於製造用於治療對發炎體之抑制有反應之疾病、病症或病況的藥劑。實例 以下實例提供用以闡釋本發明，且不應理解為對其具有限制性。在該等實例中，除非另有說明，否則所有份數及百分數皆係以重量計。下文記錄實例中之縮寫。縮寫 實例 1 ：化合物 1 之合成 . ( N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺)方法 A ： 將N,N-二甲基吡啶-4-胺(0.517 mmol, 0.063 g)溶解於THF (1.5mL)中且隨後緩慢添加二碳酸二第三丁基酯(0.492 mmol, 0.113 mL)於THF (1.5mL)中之溶液。攪拌幾分鐘後，添加1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(0.492 mmol, 0.085 g)於THF (1mL)中之溶液並將混合物攪拌30 min。同時，用氫化鈉(0.492 mmol, 0.018 g)處理THF (1mL)中之6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(0.492 mmol, 100 mg)並攪拌30 min。此時，混合兩種溶液並將其攪拌18 h。 隨後用NH4 Cl (10mL)淬滅反應並用EtOAc (10mL)稀釋。分離各層並用EtOAc (10mL)萃取水層。隨後用水(10mL)洗滌合併之有機萃取物並濃縮。將所得固體懸浮於MeOH (5mL)中，過濾，並藉由prep HPLC (10-40% MeCN:10mM aq.NH3 )純化濾液。合併經純化部分並濃縮，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(化合物1) (3.5 mg, 1.768%)。[M+H]+ 實驗值403。1 H-NMR (400 MHz；MeOD): δ 7.67 (s, 1H), 6.93 (d,J = 0.9 Hz, 1H), 6.93 (d,J = 0.9 Hz, 1H), 4.42 (t,J = 5.3 Hz, 2H), 4.42 (t,J = 5.3 Hz, 2H), 4.16 (t,J = 6.2 Hz, 2H), 4.16 (t,J = 6.2 Hz, 2H), 2.86 (t,J = 7.4 Hz, 4H), 2.86 (t,J = 7.4 Hz, 4H), 2.74-2.71 (m, 4H), 2.74-2.71 (m, 4H), 2.31-2.25 (m, 3H), 2.31-2.25 (m, 3H), 2.08-2.00 (m, 6H), 2.08-2.00 (m, 6H).方法 B ： TCPC 之製備 在N2 下將2,4,6-三氯-苯酚(50 g, 250 mmol)及吡啶(20.5 mL, 250 mmol)於醚(800 mL)中之溶液冷卻至-78℃。冷卻後，在混合物中形成固體。向混合物中緩慢添加SO2 Cl2 (21 mL, 250 mmol)。隨後將反應於r.t.下攪拌過夜。經由矽藻土墊過濾反應混合物並用醚(300 mL)沖洗。在低於40℃下濃縮醚溶液。藉由矽膠管柱(己烷 ~ PE)純化殘餘物，從而產生無色油狀TCPC (55 g，產率75%)。1 H NMR (400 MHz, CDCl3 ): δ = 7.45 (s, 2H)。步驟 1 將1,2-二氫-吡唑-3-酮(4.0 g, 47.6 mmol)及K2 CO3 (23.0 g, 166.7 mmol)在DMF (80 mL)中加熱至130℃。添加1,3-二溴丙烷(11.6 g, 57.1 mmol)並將混合物加熱3 hr且隨後濃縮。將殘餘物分配在乙酸乙酯(100 mL)與水(100 mL)之間並分離各層。用EA (50 mL)萃取水層且用鹽水(50 mL)洗滌合併之有機層，經Na2 SO4 乾燥，過濾並在真空中濃縮。藉由矽膠管柱(PE/EA = 1/2)純化殘餘物，從而產生黃色油狀6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(3.0 g，產率：51%)。1 H NMR (400 MHz, CDCl3 ): δ = 7.31 (d,J = 2.0 Hz, 1H), 5.48 (d,J = 2.0 Hz, 1H), 4.28 (t,J = 5.2 Hz, 2H), 4.18 (t,J = 6.2 Hz, 2H), 2.29-2.22 (m, 2H)。步驟 2 於0℃下向6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(3.0 g, 24.3 mmol)於MeCN (40 mL)中之溶液中逐份添加NBS (4.4 g, 24.7 mmol)並於室溫下將反應攪拌2 hr。過濾混合物並藉由反相管柱(5% - 95% H2 O中之MeCN)純化，從而產生黃色固體狀3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(3.6 g，產率：74%)。1 H NMR (400 MHz, CDCl3 ): δ = 7.30 (s, 1H), 4.36 (t,J = 5.2 Hz, 2H), 4.17 (t,J = 6.2 Hz, 2H), 2.30-2.24 (m, 2H)。步驟 3 於-78℃下在N2 下向3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.8 g, 8.9 mmol)於無水THF (15 mL)中之溶液中緩慢添加己烷中之n-BuLi (2.5 M, 3.5 mL, 8.9 mmol)。在冷卻下攪拌20 min後，於此溫度下緩慢添加醚中之ZnCl2 (1 M, 8.9 mL, 8.9 mmol)。移除冷浴並將反應於r.t.下攪拌1 hr。隨後於0℃下添加TCPC (2.6 g, 8.9 mmol)並於r.t.下攪拌1 hr。將反應用飽和NH4 Cl溶液(10 mL)淬滅並分配在水(80 mL)與EA (80 mL)之間。將有機層用鹽水(80 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色油狀粗製6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯-苯基酯，其未經任何純化即用於下一步驟。步驟 4 將6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯-苯基酯(粗製，約8.9 mmol)、NH4 OH (10 mL)及THF (10 mL)之混合物於60℃下攪拌過夜。在減壓下濃縮反應直至剩餘10 mL液體。將剩餘之溶液用1 N HCl酸化至pH = 5並分配在EA (10 mL)與水(50 mL)之間。藉由反相管柱(MeCN/H2 O)純化水層，從而產生淺黃色固體狀6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(650 mg，產率：經2個步驟36%)。1 HNMR (400 MHz, DMSO-d6 ): δ = 7.47 (s, 1H), 7.09 (brs, 2H), 4.40 (t,J = 5.2 Hz, 2H), 4.25 (t,J = 6.0 Hz, 2H), 2.22-2.14 (m, 2H)。MS: m/z 203.9 (M+H+ )。步驟 5 向6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(120 mg, 0.6 mmol)於THF (10 mL)中之溶液中添加MeONa (40 mg, 0.7 mmol)並於r.t.下攪拌20 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(110 mg, 0.6 mmol)及TEA (120 mg, 1.2 mmol)於THF (10 mL)中之溶液中一次性添加三光氣(120 mg, 0.4 mmol)並於r.t.下在N2 下攪拌20 min。隨後過濾反應混合物。向上述鈉鹽懸浮液中添加濾液並於r.t.下攪拌20 min。其後，將反應溶液分配在EA (60 mL)與水(60 mL)之間。用濃HCl將水相酸化至pH=5並用EA (60 mL)萃取。將有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮，直至出現白色固體。藉由過濾收集所形成固體並乾燥，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(57 mg，產率：22%)。1 HNMR (400 MHz, DMSO-d6 ): δ = 10.46 (brs, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.42 (t,J = 5.2 Hz, 2H), 4.25 (t,J = 5.8 Hz, 2H), 2.79 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.6 Hz, 4H), 2.22-2.18 (m, 2H), 1.99-1.92 (m, 4H)。MS: m/z 403.0 (M+H+ )。實例 2 ： 化合物 2 之合成 . N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)甲烷磺醯胺：向甲烷磺醯胺(95 mg, 1.0 mmol)於THF (5 mL)中之溶液中添加NaH (60%, 45 mg, 1.1 mmol)並於室溫下攪拌10 min，從而產生鈉鹽懸浮液。 向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(173 mg, 1.0 mmol)及TEA (0.5 mL, 3.5 mmol)於THF (10 mL)中之溶液中一次性添加三光氣(120 mg, 0.4 mmol)並將混合物於室溫下在N2 下攪拌20 min。隨後過濾反應混合物。將濾液添加至上述鈉鹽懸浮液中並於室溫下攪拌30 min。其後，將反應溶液分配在乙酸乙酯(50 mL)與水(100 mL)之間。過濾水相並用aq.HCl (1N)酸化至pH = 5。藉由過濾收集所形成固體並乾燥，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)甲烷磺醯胺(130 mg，產率：44%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.19 (brs, 1H), 8.13 (s, 1H), 6.96 (s, 1H), 3.26 (s, 3H), 2.82 (t,J = 7.2 Hz, 4H), 2.71 (t,J = 7.2 Hz, 4H), 2.03-1.94 (m, 4H)。MS: m/z 295.0 (M+H+ )。實例 3 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 硫代胺甲醯基 )-6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)硫代胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(350 mg, 2 mmol)於THF (20 mL)中之溶液中添加硫光氣(233 mg, 2 mmol)及TEA (612 mg, 6 mmol)。將反應混合物於室溫下攪拌過夜且隨後在真空中蒸發。將殘餘物稀釋於飽和NaHCO3 (50 mL)中並用EA (50 mL ×3)萃取水相。合併有機萃取物，經無水Na2 SO4 乾燥並在真空中濃縮，從而產生作為粗產物之4-異氰硫基-1,2,3,5,6,7-六氫-s -二環戊二烯并苯，其不經進一步純化即用於下一步驟。步驟 2 向6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-磺酸醯胺(60 mg, 0.3 mmol)於DMF (5 mL)中之溶液中添加4-異氰硫基-1,2,3,5,6,7-六氫-s -二環戊二烯并苯(64.5 mg, 0.3 mmol)及NaH (60%於礦物油中, 24 mg, 0.6 mmol)。將反應於室溫下攪拌2 hr (藉由LC-MS監測)並藉由H2 O (20 mL)淬滅。將混合物由1 M HCl酸化至pH = 3並用EA (20 mL ×3)萃取。合併有機相，經無水Na2 SO4 乾燥並在真空中蒸發。藉由pre-HPLC純化殘餘物，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)硫代胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(30 mg，產率：24.2%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.62 (s, 1H), 7.21-6.96 (m, 2H), 4.40-4.35 (m, 2H), 4.11-4.08 (m, 2H), 2.80 (t,J = 7.2 Hz, 4H), 2.63-2.58 (m, 4H), 2.19-2.16 (m, 2H), 1.98-1.91 (m, 4H)。MS: m/z 417.0 (M-H+ )。實例 4 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-4,5,6,7- 四氫吡唑并 [1,5-a] 吡啶 -3- 磺醯胺之 合成： 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]吡啶-3-磺醯胺之合成。 步驟 1 於-78℃下在N2 下向3-溴-4,5,6,7-四氫-吡唑并[1,5-a]吡啶(1 g, 5 mmol)於無水THF (10 mL)中之溶液中緩慢添加己烷中之n-BuLi (2.5 M, 2 mL, 5 mmol)。在冷卻下攪拌20 min後，於此溫度下緩慢添加醚中之ZnCl2 (1 M, 5 mL, 5 mmol)。移除冷浴並將反應於室溫下攪拌1 hr。隨後添加TCPC (1.8 g, 5 mmol)並將反應溶液於室溫下攪拌1 hr。將反應物分配在水(80 mL)與EA (80 mL)之間。將有機層用鹽水(80 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色凝膠狀粗製4,5,6,7-四氫-吡唑并[1,5-a]吡啶-3-磺酸2,4,6-三氯-苯基酯，其未經任何純化即用於下一步驟。步驟 2 將4,5,6,7-四氫-吡唑并[1,5-a]吡啶-3-磺酸2,4,6-三氯-苯基酯(粗製，約5 mmol)、NH3. H2 O (15 mL)及THF (15 mL)之混合物於60℃下攪拌過夜。在減壓下濃縮反應。將剩餘溶液用1 N HCl酸化至pH = 5並分配在EA (15 mL)與水(70 ml)之間。藉由反相管柱純化水相，從而產生黃色固體狀4,5,6,7-四氫-吡唑并[1,5-a]吡啶-3-磺酸醯胺(270 mg，產率：經2個步驟27%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.62 (s, 1H), 7.15 (brs, 2H), 4.08 (t,J = 6.0 Hz, 2H), 2.90 (t,J = 6.4 Hz, 2H), 1.98-1.92 (m, 2H), 1.83-1.77 (m, 2H)。MS: m/z 201.9 (M+H+ )。步驟 3 此步驟類似於N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例1)之一般程序。 HNMR (400 MHz, DMSO-d 6): δ = 10.54 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 6.94 (s, 1H), 4.09 (t,J = 5.6 Hz, 2H), 2.97 (t,J = 6.4 Hz, 2H), 2.78 (t,J = 7.6 Hz, 4H), 2.57 (t,J = 7.6 Hz, 4H), 1.98-1.90 (m, 6H), 1.82-1.78 (m, 2H)。MS: m/z 401.0 (M+H+ )。實例 5 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-5',7'- 二氫螺 [ 氧雜環丁烷 -3,6'- 吡唑并 [5,1-b][1,3] 噁嗪 ]-3'- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-5',7'-二氫螺[氧雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺醯胺之合成。標題化合物係使用N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例1)之一般程序製備。1 H NMR (400 MHz, DMSO-d 6): δ = 7.77 (s, 1H), 7.51 (s, 1H), 6.85 (s, 1H), 4.59 (s, 2H), 4.50 (d,J = 6.0 Hz, 2H), 4.43 (d,J = 6.4 Hz, 2H), 4.38 (s, 2H), 2.76 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.4 Hz, 4H), 1.94-1.90 (m, 4H)。MS: m/z 445.0 (M+H+ )。實例 6 ： N-((2,6- 二異丙基苯基 ) 胺甲醯基 )-6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。將6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(0.123 mmol, 0.025 g)懸浮於THF (1mL)中並冷卻至0℃。添加NaH (0.123 mmol, 2.95 mg)並將混合物攪拌5 min。隨後添加2-異氰酸基-1,3-二異丙基苯(0.123 mmol, 0.026 mL)並將混合物於室溫下攪拌2h。此時，用水淬滅反應並蒸發有機溶劑。隨後將反應用HCl酸化並過濾白色沈澱，用水洗滌並乾燥，從而產生N-((2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(38 mg, 76%)。1 H-NMR (400 MHz；DMSO-d6 ): δ 10.60 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.24 (t,J = 7.7 Hz, 1H), 7.12 (d,J = 7.7 Hz, 2H), 4.46-4.44 (m, 2H), 4.11 (dd,J = 7.5, 4.7 Hz, 2H), 2.91 (t,J = 6.9 Hz, 2H), 2.23-2.20 (m, 2H), 1.13-1.01 (m, 12H)。MS: m/z 407 (M+H+ )。實例 7 ： N-((4- 氯 -2,6- 二異丙基苯基 ) 胺甲醯基 )-6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((4-氯-2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。將6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(0.105 mmol, 0.021 g)溶解於THF (2mL)中並於0℃下用NaH (0.105 mmol, 4.21 mg)處理。幾分鐘後，添加5-氯-2-異氰酸基-1,3-二異丙基苯(0.105 mmol, 25 mg)並將混合物攪拌週末。隨後用水淬滅反應並將溶劑減少至初始體積之約1/3。隨後將反應用1M HCl酸化並過濾微細白色沈澱，用水洗滌並乾燥，從而產生N-((4-氯-2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(23.7 mg, 51.1%)。1 H-NMR (400 MHz；DMSO-d6 ): δ 10.70 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.15 (s, 2H), 4.45 (dd,J = 5.4, 4.8 Hz, 2H), 4.11 (t,J = 6.1 Hz, 2H), 3.62-3.59 (m, 3H), 2.93-2.86 (m, 2H), 2.24-2.20 (m, 2H), 1.78-1.75 (m, 3H), 1.11-1.01 (m, 13H)。MS: m/z 442 (M+H+ )。實例 8 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-6,6- 二甲基 -6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於0℃下向PPh3 (252.0 g, 961.5 mmol)於乙腈(600 mL)中之懸浮液中逐滴添加Br2 (49.3 mL, 961.5 mmol)於乙腈(200 mL)中之溶液，隨後添加2,2-二甲基-丙烷-1,3-二醇(50.0 g, 480.8 mmol)。將反應混合物加熱至85℃，並回流16 hr。在真空中移除溶劑。用(PE/EA = 3/1, 300 mL)洗滌殘餘固體並過濾。濃縮濾液並蒸餾，從而產生無色油狀1,3-二溴-2,2-二甲基-丙烷(45.0 g，產率：41%)。1 HNMR (300 MHz, CDCl3 ): δ = 3.42 (s, 4H), 1.18 (s, 6H)。步驟 2 將1,2-二氫-吡唑-3-酮(25.0 g, 297.6 mmol)及K2 CO3 (144.0 g, 1041.7 mmol)在DMF (700 mL)中加熱至120℃。添加1,3-二溴-2,2-二甲基-丙烷(82.0 g, 357.1 mmol)並將混合物加熱24 hr。在真空中移除溶劑。將殘餘物分配在EA/H2 O (200 mL /500 mL)之間並分離各層。用EA (200 mL)萃取水層並用鹽水(100 mL)洗滌合併之有機層，經Na2 SO4 乾燥並濃縮。將殘餘物冷卻至5℃並用PE (100 mL)洗滌，從而產生黃色固體狀6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(14.0 g，產率：31%)。1 HNMR (300 MHz, CDCl3 ): δ = 7.32 (s, 1H), 5.48 (s, 1H), 3.87 (s, 2H), 3.84 (s, 2H), 1.13 (s, 6H)。步驟 3-5 該三個步驟類似於N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例1)之一般程序。步驟 6 向6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(400 mg, 1.7 mmol)於THF (10 mL)中之懸浮液中添加MeONa (190 mg, 3.5 mmol)並將混合物於室溫下攪拌20 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(300 mg, 1.7 mmol)及TEA (530 mg, 5.2 mmol)於THF (15 mL)中之溶液中一次性添加三光氣(210 mg, 0.7 mmol)並將混合物於室溫下在N2 下攪拌20 min。隨後過濾反應混合物。將濾液添加至上述鈉鹽懸浮液中並於室溫下攪拌16 hr。其後，將反應溶液分配在EA (50 mL)與水(150 mL)之間。過濾水相並由N2 鼓泡5 min，隨後用濃HCl酸化至pH = 5。在添加MeCN (50 mL)後，溶解所形成固體。並於40℃下濃縮混合物以移除MeCN。藉由過濾收集所形成固體並乾燥，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(320 mg，產率：43%)。1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.49 (s, 1H), 7.90 (s, 1H), 7.64 (s, 1H), 6.93 (s, 1H), 4.14 (s, 2H), 3.88 (s, 2H), 2.78 (t,J = 7.2 Hz, 4H), 2.58 (t,J = 7.2 Hz, 4H), 1.98-1.90 (m, 4H), 1.02 (s, 6H)。MS: m/z 431.0 (M+H+ )。實例 9 ： 6,6- 二甲基 -6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺酸醯胺之合成 下文顯示合成6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺之另一方法。 步驟 1 於0℃下向ClSO3 H (25 mL)中逐份添加6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(3.0 g, 19.7 mmol)。於80℃下攪拌16 hr後，將反應混合物逐滴添加至冰水(250 mL)中並用EA (100 mL x3)萃取。將合併之有機層用鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。將殘餘物冷卻至5℃並用PE/EA (5/1, 30 mL)洗滌，從而產生黃色固體狀6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯(2.4 g，產率：49%)。1 HNMR (300 MHz, CDCl3 ): δ = 7.79 (s, 1H), 4.16 (s, 2H), 3.90 (s, 2H), 1.20 (s, 6H)。步驟 2 向6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯(2.2 g, 8.8 mmol)於THF (18 mL)中之溶液中添加NH3 .H2 O (10 mL)。於60℃下攪拌1 hr後，將反應混合物濃縮至乾燥。將殘餘物用MeOH (20 mL)稀釋並由aq.HCl (2 N)酸化至pH = 5。藉由反相管柱(0% - 60% H2 O中之MeCN)純化所得溶液，從而產生黃色固體狀6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(1.6 g，產率：79%)。實例 10 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-6- 羥基 -6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向1,3-二溴-丙-2-醇(42.5 g, 0.19 mol)及DHP (33 g, 0.38 mol)於DCM (300 mL)中之溶液中逐份添加TsOH (3.6 g, 0.019 mol)並將混合物於室溫下攪拌2 hr。濃縮反應溶液並藉由矽膠管柱(PE/EA = 50/1)純化殘餘物，從而產生無色油狀2-(2-溴-1-溴甲基-乙氧基)-四氫-吡喃(34 g，產率：60%)。1 H NMR (300 MHz, DMSO-d6 ): δ = 4.80-4.79 (m, 1H), 4.04-3.90 (m, 2H), 3.72-3.52 (m, 5H), 1.87-1.55 (m, 6H)。步驟 2 將2-(2-溴-1-溴甲基-乙氧基)-四氫-吡喃(17 g, 56.3 mmol)、1,2-二氫-吡唑-3-酮(4 g, 47 mmol)及K2 CO3 (23 g, 165 mmol)於DMF (250 mL)中之混合物於100℃下攪拌過夜。在減壓下移除溶劑。將殘餘物分配在EA (200 mL)與水(200 ml)之間。用EA (200 ml)萃取水相。合併有機層，用水(100 mL)及鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(EA)純化殘餘物，從而產生黃色油狀6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(4.9 g，產率：46%)。1 H NMR (300 MHz, DMSO-d6 ): δ = 7.34 (s, 1H), 5.51 (s, 1H), 4.89-4.83 (m, 1H), 4.36-4.24 (m, 4H), 3.93-3.88 (m, 1H), 3.59-3.54 (m, 1H), 1.79-1.69 (m,3H), 1.65-1.51 (m,4H)。MS: m/z 224.9 (M+H+ )。步驟 3 於0℃下在N2 下向6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(5.1 g, 22.8 mmol)於MeCN中之溶液中，取NBS分成兩份添加。隨後將反應於室溫下攪拌1 hr。將反應物分配在EA (100 mL)與水(200 mL)之間。將有機層用水(100 mL)及鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生黃色固體狀3-溴-6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(5.6 g，產率：81%)。1 H NMR (300 MHz, DMSO-d6 ): δ = 7.33 (s, 1H), 4.88-4.82 (m, 1H), 4.48-4.18 (m, 5H), 3.88-3.75 (m, 1H), 3.58-3.53 (m, 1H), 1.84-1.51 (m,7H)。MS: m/z 303.0 (M+H+ )。步驟 4 於-78℃下在N2 下向3-溴-6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(2 g, 6.6 mmol)於無水THF (20 mL)中之溶液中緩慢添加己烷中之n-BuLi (2.5 M, 2.6 mL, 6.6 mmol)。在冷卻下攪拌20 min後，於此溫度下緩慢添加醚中之ZnCl2 (1 M, 6.6 mL, 6.6 mmol)。移除冷浴並將反應於室溫下攪拌1 hr。隨後添加TCPC (2 g, 6.6 mmol)並將混合物於室溫下攪拌1 hr。將反應物分配在水(100 mL)與EA (100 mL)之間。將有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色凝膠狀粗製6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯-苯基酯，其未經任何純化即用於下一步驟。步驟 5 將6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯-苯基酯(粗製，約6.6 mmol)、NH4 OH (20 mL)及THF (20 mL)之混合物於60℃下攪拌過夜。在減壓下濃縮反應直至剩餘10 mL液體。將剩餘溶液用1 N HCl酸化至pH = 5並用EA (100 mL x5)萃取。合併有機層，經Na2 SO4 乾燥並濃縮，從而產生黃色凝膠狀粗製6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺，其未經任何純化即用於下一步驟。MS: m/z 304.1 (M+H+ )。步驟 6 向6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(粗製, 6.6 mmol)於THF/H2 O/EtOH (50 mL/10 mL/50 mL)中之溶液中添加濃HCl (10 mL)並於室溫下攪拌過夜。在減壓下濃縮反應。藉由反相管柱(MeCN/H2 O)純化殘餘物，從而產生白色固體狀6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(290 mg，產率：經3個步驟21%)。1 H NMR (300 MHz, DMSO-d6 ): δ = 7.48 (s, 1H), 7.11 (brs, 2H), 5.65 (brs, 1H), 4.30-4.20 (m, 4H), 3.96-3.92 (m, 1H)。MS: m/z 220.1 (M+H+ )。步驟 7 向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(63.1 mg, 0.365 mmoL)及TEA (0.203 ml，1.1 mmoL)於THF (5 ml)中之溶液中添加三光氣(43.7 mg, 0.146 mmoL)，並將混合物於室溫下攪拌10 min。在另一圓底燒瓶中，向6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(80 mg, 0.365 mmoL)於THF (5 ml)中之溶液中添加MeONa (21.7 mg, 0.401 mmoL)並將混合物於室溫下攪拌20 min。過濾所製備之4-異氰酸基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯以移除所得沈澱並將濾液添加至含有磺醯胺鹽之另一燒瓶中。藉由TLC檢查反應並在20 min後利用添加水(30 mL)淬滅。用EA (20 mL)洗滌水相且稍後過濾。將濾液酸化至pH = 3~4。藉由過濾收集所得固體，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(15 mg，產率：10%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.67 (s, 1H), 4.34 (s, 3H), 4.24 (dd,J = 4.0, 3.2 Hz, 1H), 3.96 (d,J = 12.4Hz, 1H), 2.78 (t,J = 7.2Hz, 4H), 2.60 (t,J = 7.6Hz, 4H), 1.98-1.93 (m, 4H)。MS: m/z 419.1 (M+H+ )。實例 11 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-5,6,7,8- 四氫吡唑并 [5,1-b][1,3] 氧氮呯 -3- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-5,6,7,8-四氫吡唑并[5,1-b][1,3]氧氮呯-3-磺醯胺之合成。 步驟 1 將1,2-二氫-吡唑-3-酮(3.0 g, 35.7 mmol)及K2 CO3 (17.0 g, 125.0 mmol)在DMF (100 mL)中加熱至130℃。添加1,4-二溴-丁烷(9.3 g, 42.9 mmol)並加熱混合物並保持16 hr。在真空中移除溶劑。將殘餘物分配在EA/H2 O (50 mL /80 mL)之間並分離各層。用EA (50 mL)萃取水層，且用鹽水(50 mL)洗滌合併之有機層，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生無色油狀5,6,7,8-四氫-4-氧雜-1,8a-二氮雜-甘菊藍(1.3 g，產率：27%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.24 (d,J = 1.5 Hz, 1H), 5.69 (d,J = 1.5 Hz, 1H), 4.25-4.20 (m, 2H), 4.06 (t,J = 5.1 Hz, 2H), 2.07-2.03 (m, 2H), 1.91-1.84 (m, 2H)。步驟 2-5 該四個步驟類似於N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例3)之一般程序。1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.60 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 6.94 (s, 1H), 4.22-4.16 (m, 4H), 2.79 (t,J = 7.6 Hz, 4H), 2.58 (t,J = 7.2 Hz, 4H), 2.03-1.90 (m, 6H), 1.80-1.70 (m, 2H)。MS: m/z 417.0 (M+H+ )。實例 12 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 將1,2-二氫-吡唑-3-酮(2.0 g, 23.8 mmol)及K2 CO3 (11.5 g, 83.3 mmol)在DMF (60 mL)中加熱至120℃。添加1,3-二溴-丁烷(6.2 g, 28.6 mmol)並加熱混合物並保持16 hr。在真空中移除溶劑。將殘餘物分配在EA/H2 O (50 mL /80 mL)之間並分離各層。用EA (50 mL)萃取水層，且用鹽水(50 mL)洗滌合併之有機層，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 5/1至1/1)純化殘餘物，從而產生黃色油狀7-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.3 g，產率：40%)及黃色固體狀5-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(500 mg，產率：15%)。 7-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪：1 HNMR (400 MHz, CDCl3 ): δ = 7.32 (d,J = 2.0 Hz, 1H), 5.45 (d,J = 1.6 Hz, 1H), 4.36-4.31 (m, 2H), 4.24-4.18 (m, 1H), 2.34-2.27 (m, 1H), 2.02-1.94 (m, 1H), 1.59 (d,J = 6.0 Hz, 3H)。 5-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪：1 HNMR (400 MHz, CDCl3 ): δ = 7.30 (d,J = 1.6 Hz, 1H), 5.45 (d,J = 2.0 Hz, 1H), 4.38-4.30 (m, 1H), 4.25-4.20 (m, 1H), 4.15-4.08 (m, 1H), 2.19-2.03 (m, 2H), 1.46 (d,J = 6.4 Hz, 3H)。步驟 2-5 該四個步驟類似於N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例1)之一般程序。1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.47 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 6.94 (s, 1H), 4.53-4.32 (m, 3H), 2.79 (t,J = 7.2 Hz, 4H), 2.58 (t,J = 7.2 Hz, 4H), 2.38-2.31 (m, 1H), 1.99-1.91 (m, 5H), 1.45 (d,J = 6.0 Hz, 3H)。MS: m/z 417.0 (M+H+ )。實例 13 ： 6- 氟 -N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示6-氟-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於-78℃下在N2 下向6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(100 mg, 0.46 mmol)於DCM (5 mL)中之溶液中添加DAST (148 mg, 0.92 mmol)。隨後於室溫下將反應物攪拌過夜。將反應用H2 O (20 mL)淬滅並分配在DCM (40 mL)與水(20 mL)之間。經Na2 SO4 乾燥有機層並濃縮。藉由反相管柱(MeCN/H2O)純化殘餘物，從而產生白色固體狀6-氟-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(18 mg，產率：18%)。MS: m/z 222.1 (M+H+ )。步驟 2 此步驟類似於N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例1)之一般程序。1 H NMR (400 MHz, DMSO-d 6): δ = 10.58 (s, 1H), 8.00 (s, 1H), 7.69 (s, 1H), 6.93 (s, 1H), 5.58 (d,J = 44.0 Hz, 1H), 4.75(t,J = 12.0 Hz, 1H), 4.59-4.37 (m, 3H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.97-1.90 (m, 4H)。MS: m/z 421.0 (M+H+ )。實例 14 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-6- 甲氧基 -6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向3-溴-6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(4.6 g, 15.2 mmol)於THF/H2 O/EtOH (50 mL/10 mL/50 mL)中之溶液中添加濃HCl。將反應於室溫下攪拌2 hr。濃縮反應溶液。將殘餘物用飽和NaHCO3 溶液處理。藉由過濾收集所形成固體，從而產生白色固體狀3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(2.76 g，產率：84%)。1 H NMR (300 MHz, DMSO-d6 ): δ = 7.36 (s, 1H), 5.59 (brs, 1H), 4.28-4.18 (m, 4H), 3.95-3.90 (m, 1H)。步驟 2 向3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(1.2 g, 5.5 mmol)於DMF (12 mL)中之溶液中添加NaH (60%於礦物油中, 263 mg, 6.6 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加MeI (940 mg, 6.6 mmol)並將混合物於室溫下攪拌2 hr。將反應混合物倒入水(60 mL)中並用EA (50 mL)萃取。將有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由反相管柱(MeCN/H2 O)純化殘餘物，從而產生白色固體狀3-溴-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1 g，產率：78%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.34 (s, 1H), 4.53-4.48 (m, 1H), 4.27-4.18 (m, 3H), 3.94-3.93 (m, 1H), 3.49 (s, 3H)。MS: m/z 232.9 (M+H+ )。步驟 3~5 該等步驟類似於N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例1)之一般程序。1 H NMR (400 MHz, DMSO-d 6): δ = 10.47 (s, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.65 (d,J = 11.6 Hz, 1H), 4.37 (d,J = 11.2 Hz, 1H), 4.24-4.22 (m, 2H), 4.06 (s, 1H), 3.34 (重疊, 3H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H)。MS: m/z 433.0 (M+H+ )。實例 15 ： N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-5- 甲基 -6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-5-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。標題化合物係使用N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(實例1)之一般程序製備。1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.51 (s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.94 (s, 1H), 4.60-4.56 (m, 1H), 4.13-4.08 (m, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.59 (t,J = 6.8 Hz, 4H), 2.28-2.24 (m, 1H), 1.98-1.93 (m, 5H), 1.38 (d,J = 6.0 Hz, 3H)。MS: m/z 417.0 (M+H+ )。實例 16 ： N-((8- 氯 -1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-6,7- 二氫 -5H- 吡唑并 [5,1-b][1,3] 噁嗪 -3- 磺醯胺之合成 下文顯示N-((8-氯-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 將1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(2.332 mmol, 404 mg)及NCS (2.332 mmol, 0.311 g)在DCM (5mL)中並攪拌過夜。隨後將混合物分配在水(20mL)與DCM (20mL)之間。分離各層且用DCM (20mL)萃取水層。隨後將合併之有機層經Na2 SO4 乾燥，過濾並濃縮，從而產生褐色固體狀1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(2.332 mmol, 404 mg)，其未經純化即使用。MS: m/z 209 (M+H+ )。步驟 2 將N,N-二甲基吡啶-4-胺(0.481 mmol, 0.059 g)溶解於THF (1.5mL)中且隨後緩慢添加二碳酸二第三丁基酯(0.481 mmol, 0.111 mL)於THF (1.5mL)中之溶液。攪拌幾分鐘後，添加8-氯-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(0.481 mmol, 100 mg)於THF (1mL)中之溶液並將混合物攪拌30 min。同時，將THF (1mL)中之6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(0.481 mmol, 0.098 g)用氫化鈉(0.481 mmol, 0.012 g)處理並攪拌30 min。此時，混合兩種溶液並攪拌18 h。 隨後將反應用飽和NH4Cl (10mL)淬滅並用EtOAc (40mL)稀釋。分離各層並用EtOAc (30mL)萃取水層。隨後將合併之有機萃取物用水(20mL)洗滌並濃縮。將所得固體懸浮於MeOH:水(10:1, 10mL)中，過濾紅色固體並棄去。濃縮濾液並藉由製備型HPLC (10-40% MeCN:10mM NH3水)純化。將經純化部分合併並濃縮，從而產生白色固體狀N-((8-氯-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(5.8 mg, 2.76%)。1 H-NMR (400 MHz；DMSO-d6 ): δ 7.88-7.85 (m, 1H), 7.55 (s, 1H), 4.42-4.39 (m, 2H), 4.11-4.08 (m, 2H), 2.85-2.82 (m, 4H), 2.71 (t, J = 7.4 Hz, 4H), 2.22-2.16 (m, 2H), 2.04-1.97 (m, 4H)。MS: m/z 437 (M+H+ )。實例 17 ： 4- 氟 -N-((1,2,3,5,6,7- 六氫 -s- 二環戊二烯并苯 -4- 基 ) 胺甲醯基 )-4,5,6,7- 四氫吡唑并 [1,5-a] 吡啶 -3- 磺醯胺之合成 下文顯示4-氟-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]吡啶-3-磺醯胺之合成。 步驟 1 向4-溴-2H-吡唑-3-甲酸乙基酯(8.0 g, 36.4 mmol)於DMF (80 mL)中之溶液中添加K2 CO3 (10 g, 72.8 mmol)及4-溴-丁酸乙基酯(10 g, 54.8 mmol)，隨後將懸浮液攪拌過夜。利用添加EA (200 mL)及水(200 mL)淬滅反應。分離有機層。用EA (200 mL)萃取水層。將有機層合併並用水(300 mL x3)、鹽水(300 mL)洗滌，且經Na2 SO4 乾燥。在真空中濃縮溶液。藉由矽膠管柱(PE/EA = 10/1)純化殘餘物，從而產生無色油狀4-溴-2-(3-乙氧基羰基-丙基)-2H-吡唑-3-甲酸乙基酯(6.7 g，產率：55.4%)。MS: m/z 332.8 (M+H+ )。步驟 2 於0℃下向4-溴-2-(3-乙氧基羰基-丙基)-2H-吡唑-3-甲酸乙基酯(6.7 g, 20.2 mmol)於THF (120 mL)中之溶液中添加NaH (1.2 g, 30.3 mmol)且隨後將混合物加熱回流過夜。在反應完成時，將反應用飽和NH4 Cl水溶液(20 mL)淬滅。用EA (100 mL x2)萃取水相。將萃取物用鹽水(100 mL)洗滌，經Na2 SO4 乾燥，並濃縮，從而產生白色固體狀3-溴-4-側氧基-4,5,6,7-四氫-吡唑并[1,5-a]吡啶-5-甲酸乙基酯(5.2 g，產率：90%)。MS: m/z 286.9 (M+H+ )。步驟 3 向3-溴-4-側氧基-4,5,6,7-四氫-吡唑并[1,5-a]吡啶-5-甲酸乙基酯(5.2 g, 15.7 mmol)於DMSO (200 mL)及水(5 mL)中之溶液中添加NaCl (5.5 g, 94 mmol)，並將混合物加熱至150℃並保持2 hr。冷卻至室溫後，用EA (200 mL)及水(200 mL)稀釋反應物。分離有機層。用EA (200 mL)萃取水層。將合併之有機層用水(300 mL x3)、鹽水(300 mL)洗滌並經Na2 SO4 乾燥。在真空中濃縮溶液。藉由矽膠管柱(PE/EA = 5/1)純化殘餘物，從而產生白色固體狀3-溴-6,7-二氫-5H-吡唑并[1,5-a]吡啶-4-酮(2.6 g，產率：66%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.55 (s, 1H), 4.40 (t,J = 6.0 Hz, 2H), 2.72 (t,J = 6.4 Hz, 2H), 2.36-2.40 (m,2H)。步驟 4 於0℃下向3-溴-6,7-二氫-5H-吡唑并[1,5-a]吡啶-4-酮(1.6 g, 7.36 mmol)於MeOH (20 mL)中之溶液中添加NaBH4 (1.4 g, 12.8 mmol)，並將混合物於室溫下攪拌2 hr。在反應完成時，蒸發反應物以移除MeOH。將殘餘物分配在EA (50 mL)與水(50 mL)之間。分離有機層。用EA (50 mL)萃取水層。將合併之有機層用鹽水(30 mL)洗滌且經Na2 SO4 乾燥。濃縮溶液，從而產生白色固體狀3-溴-4,5,6,7-四氫-吡唑并[1,5-a]吡啶-4-醇(1.4 g，產率：88%)。MS: m/z 216.9 (M+H+ )。步驟 5 於-60℃下向3-溴-4,5,6,7-四氫-吡唑并[1,5-a]吡啶-4-醇(1.4 g, 6.5 mmol)於DCM (30 mL)中之溶液中添加DAST (2.1 g, 13 mmol)。將溶液緩慢升溫至室溫，並於室溫下攪拌2 hr。在反應完成時，向混合物中添加DCM (50 mL)及水(50 mL)。分離有機層。用DCM (50 mL)萃取水層。將合併之有機層用鹽水(50 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。藉由矽膠管柱(PE/EA = 5/1)純化殘餘物，從而產生黃色油狀3-溴-4-氟-4,5,6,7-四氫-吡唑并[1,5-a]吡啶(830 mg，產率：59%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.50 (s, 1H), 5.60 (dt,J = 51.2, 2.8 Hz,1H), 4.28-4.32 (m,1H), 3.87-3.94 (m,1H), 2.26-2.40 (m,2H), 1.92-2.00 (m,2H)。步驟 6 於-78℃下在N2 保護下向3-溴-4-氟-4,5,6,7-四氫-吡唑并[1,5-a]吡啶(0.5 g, 2.3 mmol)於無水THF (5 mL)中之溶液中緩慢添加己烷中之n-BuLi (0.92 mL, 2.3 mmol, 2.5 M)，於此溫度下攪拌20 min後，於此溫度下緩慢添加醚中之ZnCl2 (2.3 mL, 2.3 mmol, 1 M)。移除冷浴並將反應於室溫下攪拌1 hr。於0℃下向混合物中添加TCPC (0.68 g, 2.3 mmol)並將混合物於室溫下攪拌1 hr。將反應用飽和NH4 Cl溶液(2 mL)淬滅並分配在水(20 mL)與EA (20 mL)之間。將有機層用鹽水(80 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色油狀粗製6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯-苯基酯。將粗製物溶解於THF (5 mL)中，並添加NH3. H2 O (5 mL)，隨後加熱至60℃過夜。在反應完成時，濃縮反應溶液以移除溶劑。將殘餘物用1 N HCl酸化至pH = 5並分配在EA (20 mL)與水(20 mL)之間。分離有機層。用EA (20 mL)萃取水層。將合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。藉由矽膠管柱(PE/EA=2/1)純化殘餘物，從而產生黃色固體狀4-氟-4,5,6,7-四氫-吡唑并[1,5-a]吡啶-3-磺酸醯胺(0.17 g，產率：34%)。MS: m/z 220.0 (M+H+ )。步驟 7 向4-氟-4,5,6,7-四氫-吡唑并[1,5-a]吡啶-3-磺酸醯胺(75 mg, 0.34 mmol)於THF (2mL)中之溶液中添加MeONa (22 mg, 0.41 mmol)並將混合物於室溫下攪拌20 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(59 mg, 0.34 mmol)及TEA (69 mg, 0.68 mmol)於THF (3 mL)中之溶液中一次性添加三光氣(141 mg, 0.14 mmol)並將混合物於室溫下在N2 下攪拌20 min。隨後過濾反應混合物。向上述鈉鹽懸浮液中添加濾液並於室溫下攪拌1hr。其後，將反應溶液分配在EA (15 mL)與水(15 mL)之間。分離水相並用1M HCl酸化至pH = 5。藉由過濾收集所得固體並風乾，從而產生白色固體狀4-氟-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]吡啶-3-磺醯胺(45 mg，產率：31.4%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 10.67 (s, 1H), 8.03 (s, 1H), 7.94(s, 1H), 6.93 (s,1H), 6.08 (d,J = 49.2 Hz,1H), 4.35-4.37 (m,1H), 4.05-4.08 (m,1H), 2.78 (t,J = 6.8 Hz, 4H), 2.55 (t,J = 6.8 Hz, 4H), 1.92-2.29 (m,8H)。MS: m/z 419.0 (M+H+ )。實例 18 下文顯示((6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉之合成。 步驟 1 ： 將1,2-二氫-吡唑-3-酮(53.0 g, 630.9 mmol)及K2 CO3 (305.0 g, 2210.1 mmol)在DMF (1 L)中加熱至130℃。添加1,3-二溴丙烷(140.0 g, 693.1 mmol)並將混合物加熱8 hr且隨後濃縮。將殘餘物分配在EA (200 mL)與水(500 mL)之間並分離各層。用EA (150 mL x8)萃取水層，且用鹽水(300 mL)洗滌合併之有機層，經Na2 SO4 乾燥，過濾並在真空中濃縮。藉由矽膠管柱(PE/EA = 3/1)純化殘餘物，從而產生黃色油狀6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(32.0 g，產率：41%)。1 H NMR (400 MHz, CDCl3 ): δ = 7.31 (d,J = 2.0 Hz, 1H), 5.48 (d,J = 2.0 Hz, 1H), 4.28 (t,J = 5.2 Hz, 2H), 4.18 (t,J = 6.2 Hz, 2H), 2.29-2.22 (m, 2H)。步驟 2 ： 於0℃下向ClSO3 H (380 mL)中逐滴添加6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(64.0 g, 516.1 mmol)。於80℃下攪拌16 hr後，將反應混合物逐滴添加至冰水/ EA (4 L/1.5 L)之混合物中。分離各層並用EA (300 mL x2)萃取水層。將合併之有機層用鹽水(500 mL)洗滌，經Na2 SO4 乾燥並濃縮。用PE (200 mL)洗滌殘餘物，從而產生黃色固體狀6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯(73.0 g，產率：63%)。步驟 3 ： 向6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯(73.0 g, 328.8 mmol)於THF (430 mL)中之溶液中添加NH3 .H2 O (180 mL)。於60℃下攪拌16 hr後，將反應混合物濃縮至乾燥。將殘餘物用aq.HCl (0.2 M, 110 mL)、H2 O (40 mL)洗滌，並乾燥，從而產生黃色固體狀6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(52.0 g，產率：78%)。1 HNMR (300 MHz, DMSO-d 6 ): δ = 7.47 (s, 1H), 7.08 (s, 2H), 4.40 (t,J = 5.1 Hz, 2H), 4.10 (t,J = 6.0 Hz, 2H), 2.23-2.15 (m, 2H)。步驟 4 ： 於0~5℃下向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(15.0 g, 87 mmol)及TEA (13.3 mL, 95.4 mmol)於THF (300 mL)中之溶液中一次性添加三光氣(8.5 g, 28.6 mmol)並將混合物於70℃下在N2 下攪拌1小時。隨後經由矽藻土過濾反應混合物。用30 mL PE洗滌濾餅。將濾液濃縮至乾燥並溶解於100 mL正己烷中。經由矽膠墊過濾混合物。將濾液濃縮至乾燥，從而產生粉色油狀4-異氰酸基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(14.6 g，產率：84%)。 將6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(14.3 g, 70.4 mmol)於MeOH (500 mL)中之懸浮液於80℃下攪拌直至得到澄清溶液，隨後添加MeONa (3.8 g, 70.4 mmol)並將混合物攪拌5 min。將溶液濃縮至乾燥並將殘餘物與MeCN (100 mL)共蒸發。將殘餘固體懸浮於MeCN (320 mL)中並添加4-異氰酸基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(14.6 g, 73.3 mmol)。將混合物於室溫下攪拌16小時並過濾。將濾餅與EtOH (250 mL)、PE/EA (5/1, 250 mL)一起研磨，從而產生產物。將產物溶解於H2 O (200 mL)中並濃縮至乾燥，從而產生白色固體狀((6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉(24.5 g，產率：82%)。1 HNMR (400 MHz, D2 O): δ = 7.64 (s, 1H), 7.02 (s, 1H), 4.40 (t,J = 5.2 Hz, 2H), 4.11 (t,J = 6.0 Hz, 2H), 2.83 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 2.28-2.22 (m, 2H), 2.04-1.96 (m, 4H)。MS: m/z 403.1 (M+H+ )。實例 19 下文顯示1-((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯 -4-基))-3-(2,3-二氫-吡唑并[5,1-b ]噁唑-7-磺醯基)-脲之合成。 步驟 1 向1,2-二氫-吡唑-3-酮(500 mg, 5.9 mmol)於MeCN (50 mL)中之溶液中添加1,2-二溴-乙烷(3.3 g, 17.6 mmol)及K2 CO3 (2.4 g, 17.6 mmol)。於回流下攪拌過夜後，過濾反應混合物，並在真空中濃縮濾液。藉由反相HPLC (H2 O中之MeCN，5%至95%)純化殘餘物，從而產生黃色固體狀2,3-二氫-吡唑并[5,1-b ]噁唑(260 mg, 40%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.27 (s, 1H), 5.37 (d,J = 1.6 Hz, 1H), 5.06 (t,J = 8.0 Hz, 2H), 4.23 (t,J = 8.0 Hz, 2H)。步驟 2 將2,3-二氫-吡唑并[5,1-b ]噁唑(1 g, 9.1 mmol)溶解於ClSO3 H (20 mL)中。於80℃下加熱過夜後，將反應混合物逐滴添加至EA (150 mL)、NH3 ·H2 O (20 mL)及H2 O (150 mL)之混合物中。於室溫下攪拌後，在真空中濃縮反應混合物。將殘餘物懸浮於MeOH (30 mL)中，攪拌0.5 h，並過濾混合物。將濾液在真空中蒸發並藉由反相HPLC (水中之MeCN，0%至60%)純化殘餘物，從而產生黃色固體狀2,3-二氫-吡唑并[5,1-b ]噁唑-7-磺酸醯胺(60 mg, 4%)。步驟 3 - 製法 E 向1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基胺(55 mg, 0.32 mmol)於THF (10 mL)中之溶液中添加三光氣(30 mg, 0.1 mmol)及TEA (48 mg, 0.48 mmol)。於室溫下攪拌2 hr後，過濾反應混合物。在真空中濃縮濾液。隨後將殘餘物溶解於THF (5 mL)中。隨後向混合物中添加2,3-二氫-吡唑并[5,1-b ]噁唑-7-磺酸醯胺(60 mg, 0.32 mmol)及NaOMe (35 mg, 0.64 mmol)。於室溫下攪拌3 hr後，將反應由H2 O (10 mL)淬滅，由3 N HCl酸化至pH = 3，並用EA (10 mL ×3)萃取。合併有機相，經無水Na2 SO4 乾燥並在真空中蒸發。藉由prep-HPLC純化殘餘物，從而產生白色固體狀1-((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基))-3-(2,3-二氫-吡唑并[5,1-b ]噁唑-7-磺醯基)-脲(6 mg, 5%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.52 (brs, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 6.91 (s, 1H), 5.21 (t,J = 8.0 Hz, 2H), 4.32 (t,J = 8.0 Hz, 2H), 2.78 (t,J = 7.2 Hz, 4H), 2.62 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H)。MS: m/z 389.0 (M+H+ )。實例 20 下文顯示(R )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺及(S )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於0℃下向外消旋 - 6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(530 mg, 2.4 mmol)及吡啶(382 mg, 4.8 mmol)於THF (10 mL)中之溶液中添加TBSOTf (702 mg, 2.7 mmol)。將反應於室溫下攪拌2 hr。將反應由H2 O (20 mL)淬滅並由1 N HCl酸化至pH = 5。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生白色固體狀6-((第三丁基二甲基矽基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(330 mg，產率：41%)。MS: m/z 334.1 (M+H+ )。步驟 2 藉由手性prep-HPLC拆分外消旋 - 6-((第三丁基二甲基矽基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(420 mg, 1.3 mmol)，從而產生兩種異構物：白色固體狀(S )-6-((第三丁基二甲基矽基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(180 mg，產率：42%)；白色固體狀(R )-6-((第三丁基二甲基矽基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(200 mg，產率：46%)。步驟 3 向(S )-6-((第三丁基二甲基矽基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(180 mg, 0.5 mmol)於THF (4 mL)中之溶液中添加濃HCl (4 mL)。於室溫下攪拌過夜後，在減壓下濃縮反應。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生白色固體狀(S )-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(115 mg，產率：97%)。MS: m/z 220.1 (M+H+ )。 (R )-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用相同程序製備。步驟 4 (S)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如本文之製法 A 中合成，從而產生白色固體狀期望產物(50 mg，產率：23%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.66 (d,J = 2.4 Hz, 1H), 4.34 (s, 3H), 4.24 (dd,J = 4.0, 3.2 Hz, 1H), 3.96 (d,J = 12.4 Hz, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H)。MS: m/z 419.0 (M+H+ )。 (R)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用相同程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.66 (d,J = 3.2 Hz, 1H), 4.34 (s, 3H), 4.27-4.23 (m, 1H), 3.96 (d,J = 13.6 Hz, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.61 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H)。MS: m/z 419.0 (M+H+ )。實例 21 下文顯示外消旋 - 6-(二甲基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向外消旋 - (3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(1.0 g, 3.2 mmol)於DCM (5 mL)中之溶液中添加TFA (5 mL)並將混合物於室溫下攪拌20 min。將反應濃縮至乾燥，從而產生黃色固體狀粗製外消旋 - 3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-胺，其未經任何純化即用於下一步驟。MS: m/z 218.0 (M+H+ )。步驟 2 向外消旋 - 3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-胺(粗製，約3.2 mmol)於MeOH (10 mL)中之溶液中添加HCHO (30%, 3.2 g, 31.5 mmol)。將混合物於室溫下攪拌2 hr，隨後添加NaBH3 CN (2.0 g, 31.5 mmol)。隨後將反應於室溫下攪拌16 hr。藉由反相HPLC (0% - 95% H2 O中之MeCN)純化反應，從而產生白色固體狀外消旋 - 3-溴-N,N-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-胺(410 mg，產率：53%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s, 1H), 4.45-4.44 (m, 1H), 4.30-4.24 (m, 2H), 4.18-4.11 (m, 1H), 3.00-2.97 (m, 1H), 2.40 (s,6H)。MS: m/z 245.9 (M+H+ )。步驟 3 - 製法 B 於-78℃下在N2 氣氛下向外消旋 - 3-溴-N,N-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-胺(400 mg, 1.6 mmol)於無水THF (5 mL)中之溶液中緩慢添加n-BuLi (2.5 M於己烷中, 0.7 mL, 1.6 mmol)。在冷卻下攪拌20 min後，於此溫度下緩慢添加ZnCl2 (1 M於醚中, 1.6 mL, 1.6 mmol)。移除冷卻浴並將反應於室溫下攪拌1 hr。隨後添加TCPC (479 mg, 1.6 mmol)並將混合物於室溫下攪拌1 hr。將反應物分配在水(30 mL)與EA (30 mL)之間。將有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色凝膠狀粗製外消旋 - 6-(二甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯，其未經純化即用於下一步驟。步驟 4 - 製法 C 將外消旋 - 6-(二甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯(粗製，約1.6 mmol)、NH4 OH (10 mL)及THF (10 mL)之混合物於60℃下攪拌過夜。在減壓下濃縮反應直至剩餘10 mL液體。將剩餘溶液用1 N HCl酸化至pH = 5。藉由反相HPLC (0% - 95% H2 O中之MeCN)純化殘餘物，從而產生白色固體狀外消旋 - 6-(二甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯(66 mg，產率：經兩個步驟16%)。或者，可將溶液濃縮至乾燥並藉由急速層析純化。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.47 (s, 1H), 7.13 (brs, 2H), 4.95-4.41 (m, 2H), 4.23-4.13 (m, 2H), 2.89-2.86 (m, 1H), 2.26 (s,6H)。步驟 5 - 製法 A 向外消旋 - 6-(二甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯(66 mg, 0.3 mmol)於THF (5 mL)中之溶液中添加MeONa (18 mg, 0.3 mmol)並將混合物於室溫下攪拌20 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(47 mg, 0.3 mmol)及TEA (55 mg, 0.5 mmol)於THF (5 mL)中之溶液中一次性添加三光氣(33 mg, 0.1 mmol)並將混合物於室溫下在N2 下攪拌20 min。隨後過濾反應混合物。向上述鈉鹽懸浮液中添加濾液並於室溫下攪拌20 min。其後，將反應溶液分配在EA (20 mL)與水(20 mL)之間。用1 N HCl將水相酸化至pH = 5。藉由過濾收集所形成固體並乾燥，從而產生白色固體狀外消旋 - 6-(二甲基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(27 mg，產率：22%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.41 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 4.37-4.22 (m, 2H), 4.11-4.09 (m, 1H), 4.03-4.01 (m, 1H), 2.83-2.82 (m, 1H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.6 Hz, 4H), 2.25 (s, 6H), 1.93-1.86 (m, 4H)。MS: m/z 446.0 (M+H+ )。實例 22 下文顯示(S )-6-(二甲基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺及(R )-6-(二甲基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 藉由手性prep-HPLC拆分外消旋 - 6-(二甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(110 mg, 0.4 mmol)從而得到白色固體狀(S )-6-(二甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(41 mg，產率：42%)及白色固體狀(R )-6-(二甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(36 mg，產率：37%)。步驟 2 (S )-6-(二甲基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 A 中合成，從而產生白色固體狀期望產物(14 mg，產率：18%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (brs, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 6.90 (s, 1H), 4.46-4.43 (m, 2H), 4.24-4.12 (m, 2H), 2.92-2.91 (m, 1H), 2.80 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.25 (s, 6H) , 1.93-1.90 (m, 4H)。MS: m/z 446.0 (M+H+ )。 (R )-6-(二甲基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係以相同方式合成，從而產生白色固體狀產物(15 mg，產率：22%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.91 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.54-4.45 (m, 2H), 4.25-4.15 (m, 2H), 2.93-2.91 (m, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.62-2.54 (m,4H), 2.27 (s, 6H) , 1.99-1.92 (m, 4H)。MS: m/z 446.0 (M+H+ )。實例 23 下文顯示(R )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺及(S )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 藉由手性管柱拆分外消旋 - 6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(460 mg)，從而產生兩種異構物： (R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(峰1, 91 mg)及(S )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(峰2, 116 mg)。步驟 2 (R )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(44 mg，產率：31%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (brs, 1H), 7.92 (brs, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.63 (d,J = 11.6 Hz, 1H), 4.36 (d,J = 11.6 Hz, 1H), 4.27-4.19 (m, 2H), 4.06 (s, 1H), 3.34 (重疊, 3H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.93 (m, 4H)。MS: m/z 433.0 (M+H+ )。 (S )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用相同程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.51 (s, 1H), 7.98 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.64 (d,J = 11.6 Hz, 1H), 4.37 (d,J = 12.0 Hz, 1H), 4.24-4.22 (m, 2H), 4.05 (s, 1H), 3.34 (重疊, 3H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H)。MS: m/z 433.0 (M+H+ )。實例 24 下文顯示(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺及(S )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 向外消旋 - 6-((四氫-2H-吡喃-2-基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(36 g, 0.161 mol)於MeOH (200 mL)及H2 O (50 mL)中之溶液中添加濃HCl (50 mL)。於室溫下攪拌1 hr後，在減壓下濃縮反應溶液。將殘餘物用飽和NaHCO3 溶液(pH = 8)處理並藉由反相HPLC (0% - 50% H2 O中之MeCN)純化，從而產生黃色固體狀外消旋 - 6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(27 g, 粗製產率：定量)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.21 (s, 1H), 5.56 (s, 1H), 5.43 (s, 1H), 4.23-4.15 (m, 4H), 3.94-3.89 (m, 1H)。步驟 2 於0℃下在N2 下向外消旋 - 6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(10 g, 71.4 mmol)於無水DMF (150 mL)中之溶液中添加NaH (60%, 4.3 g, 107 mmol)。於室溫下攪拌1 hr後，向反應中添加MeI (15.2 g, 107 mml)。將反應於室溫下攪拌過夜，倒入水(100 mL)中並過濾。乾燥濾餅，從而產生黃色固體狀外消旋 - 6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(5.5 g，產率：50%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.21 (s, 1H), 5.44 (s, 1H), 4.44-4.40 (m, 1H), 4.23-4.10 (m, 3H), 3.96 (s, 1H), 3.34 (重疊, 3H)。步驟 3 藉由手性管柱拆分外消旋 - 6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(5.5 g)，從而產生兩種異構物： 白色固體狀(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(峰1, 2.4 g)及白色固體狀(S )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(峰2, 2.5 g)。步驟 4 在冰冷卻下向(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(2.4 g, 15.6 mmol)於MeCN中之溶液中逐份添加NBS (2.78 g, 15.6 mmol)。於室溫下攪拌1 hr後，藉由反相HPLC (MeCN/H2 O)純化反應溶液，從而產生(R )-3-溴-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(2.6 g，產率：72%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s, 1H), 4.52-4.48 (m, 1H), 4.32-4.20 (m, 3H), 3.93-3.92 (m, 1H), 3.49 (s, 3H)。 (S )-3-溴-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪係使用相同程序製備。步驟 5 (R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經任何純化即用於下一步驟。 (S )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用相同程序製備。步驟 6 (R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 C 中合成，從而產生黃色固體狀期望產物(800 mg，產率：經2個步驟32%)。MS: m/z 234.0 (M+H+ )。 (S )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用相同程序製備。步驟 7 - 製法 D 向(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(800 mg, 3.43 mol)於THF (10 mL)中之溶液中添加MeONa (370 mg, 6.86 mmol)。將混合物於室溫下攪拌30 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(891 mg, 5.1 mol)及TEA (1.5 g, 15.3 mmol)於THF (20 mL)中之溶液中一次性添加三光氣(611 mg, 2.1 mmol)。於室溫下在N2 下攪拌30 min後，過濾反應混合物。向上述鈉鹽懸浮液中添加濾液並將反應於室溫下攪拌過夜。其後，將反應溶液分配在EA (50 mL)與水(80 mL)之間。藉由反相HPLC (MeCN/H2 O)純化水相，從而產生黃色固體狀(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(250 mg，產率：16%)。1 H NMR (400 MHz, D2 O): δ = 7.52 (s, 1H), 6.88 (s, 1H), 4.51 (d,J = 12.0 Hz, 1H), 4.16-4.11 (m, 3H), 4.02-4.00 (m, 1H), 3.30 (s, 3H), 2.68 (t,J = 7.2 Hz, 4H), 2.51 (t,J = 7.6 Hz, 4H), 1.90-1.81 (m, 4H)。MS: m/z 433.1 (M+H+ )。 (S )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉係使用相同程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.47 (brs, 1H), δ = 7.39 (s, 1H), 6.78 (s,1H), 4.49 (dt,J = 8.0 Hz, 2.0 Hz, 1H), 4.23-4.15 (m,2H), 4.14-4.08 (m,1H), 3.99-3.95 (m,1H), 3.34 (s,3H), 2.75 (t,J = 7.2 Hz, 4H), 2.65 (t,J = 7.2 Hz, 4H), 1.96-1.86 (m,4H)。MS: m/z 433.1(M+H+ )。實例 25 下文顯示(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 將1,2-二氫-吡唑-3-酮(50.0 g, 600 mmol)於吡啶(300 mL)中之溶液加熱至95℃。經0.5小時向該溶液中緩慢添加乙酸酐(61.2 g, 600 mmol)於吡啶(100 mL)中之溶液。將反應於95℃下再加熱1 hr。將反應混合物在真空中濃縮，從而產生深紅色油，將其與MeOH (150 mL)一起研磨並過濾，從而產生白色固體狀1-乙醯基-1,2-二氫-吡唑-3-酮(54.0 g，產率：71%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 10.92 (s, 1H), 8.08 (s, 1H), 5.96 (s, 1H), 2.45 (重疊, 3H)。步驟 2 在N2 下將1-乙醯基-1,2-二氫-吡唑-3-酮(34.7 g, 280 mol)及PPh3 (24.9 g, 420 mol)於THF (400 mL)中之混合物冷卻至0℃。向混合物中緩慢添加DIAD (84.8 g, 420 mmol)。於0℃下將反應再攪拌1小時，隨後緩慢添加(R )-環氧乙-2-基甲醇(25.2 g, 340 mmol)。隨後將反應物於室溫下攪拌過夜。將反應混合物在真空中濃縮並藉由矽膠管柱(PE/EA = 10/1)純化殘餘物，從而產生白色固體狀(R )-1-乙醯基-2-(環氧乙-2-基甲基)-1H-吡唑-3(2H)-酮(34.8 g，產率：68%)。1 H NMR (400 MHz, CDCl3 ): δ = 8.06 (d,J = 2.8 Hz, 1H), 6.00 (d,J = 3.2 Hz, 1H), 4.55 (dd,J = 12.0, 3.2 Hz, 1H), 4.20 (dd,J = 12.0, 3.2 Hz, 1H), 3.39 (q,J = 3.2 Hz, 1H), 2.92 (t,J = 4.4 Hz, 1H), 2.76 (dd,J = 4.4, 2.4 Hz, 1H), 2.57 (s, 3H)。步驟 3 於室溫下向(R )-1-乙醯基-2-(環氧乙-2-基甲基)-1H-吡唑-3(2H)-酮(34.8 g, 190 mmol)於AcOH (34.2 g, 570 mmol)及THF (200 mL)中之溶液中添加LiCl (13.1 g, 310 mmol)。隨後將反應物於室溫下攪拌過夜。將反應物分配在EA (200 mL)與水(200 mL)之間。將有機層用飽和NaHCO3 (100 mL)及鹽水(100 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮，從而產生無色油狀粗製(R )-1-乙醯基-2-(3-氯-2-羥丙基)-1H-吡唑-3(2H)-酮，其未經任何純化即用於下一步驟。1 H NMR (300 MHz, DMSO-d 6 ): δ = 8.25 (d,J = 2.7 Hz, 1H), 6.23 (d,J = 3.0 Hz, 1H), 5.59 (brs, 1H), 4.24-4.19 (m, 2H), 4.07-4.04 (m, 1H), 3.75-3.62 (m,2H), 2.50 (重疊, 3H)。MS: m/z 219.4 (M+H+ )。步驟 4 將(R )-1-乙醯基-2-(3-氯-2-羥丙基)-1H-吡唑-3(2H)-酮(粗製, 190 mmol)及K2 CO3 (78.7 g, 570 mmol)於DMF (400 mL)中之混合物於135℃下攪拌過夜。在減壓下移除溶劑。藉由矽膠管柱(EA)純化殘餘物，從而產生白色固體狀(R )-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(12.8 g，產率：48%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.21 (d,J = 1.6 Hz, 1H), 5.51 (d,J = 3.2 Hz, 1H), 5.44 (d,J = 1.6 Hz, 1H), 4.24-4.13 (m, 4H), 3.92 (d,J = 12.4 Hz, 1H)。步驟 5 於0℃下在N2 下向(R )-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(12.8 g, 91.4 mmol)於MeCN (200 mL)中之溶液中，取NBS (17.9 g, 100.6 mmol) 分成兩份添加。隨後將反應於室溫下攪拌1 hr。將反應物分配在EA (200 mL)與水(200 mL)之間。將有機層用飽和NaHCO3 (100 mL)及鹽水(100 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。將殘餘物與EA (50 mL)一起研磨並過濾，從而產生白色固體狀(R )-3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(11.3 g，產率：57%)。MS: m/z 219.3 (M+H+ )。步驟 6 向(R )-3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(12.2 g, 55.7 mmol)於DMF (60 mL)中之溶液中添加NaH (60%於礦物油中，2.7 g, 66.8 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加MeI (9.5 g, 66.8 mmol)。於室溫下攪拌2 hr後，將反應物倒入水(200 mL)中並用EA (100 mLx2)萃取。將有機層用水(100 mL)及鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮。將殘餘物與MeOH/H2 O (2/1, 100 mL)一起研磨並過濾，從而產生白色固體狀(R )-3-溴-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(9.5 g，產率：73%)。MS: m/z 233.3 (M+H+ )。步驟 7 (R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經任何純化即用於下一步驟。 (R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 C 中合成，從而產生白色固體狀期望產物(2.6 g，產率：經2個步驟27%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.47 (s, 1H), 7.08 (s, 2H), 4.58-4.54 (m, 1H), 4.32-4.18 (m, 3H), 4.01 (d,J = 1.2 Hz, 1H), 3.35 (重疊, 3H)。步驟 8 於0℃下向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(15.0 g, 87 mmol)及TEA (13.3 mL, 95.4 mmol)於THF (30 mL)中之溶液中一次性添加三光氣(8.5 g, 28.6 mmol)並將混合物於70℃下在N2 下攪拌1 hr。隨後經由矽藻土過濾反應混合物。用30 mL PE洗滌濾餅。將濾液濃縮至乾燥並溶解於100 mL正己烷中。經由矽膠墊過濾混合物。將濾液濃縮至乾燥，從而產生粉色油狀4-異氰酸基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(14.1 g，產率：81%)。 將(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(1.6 g, 6.9 mmol)於MeOH (30 mL)中之懸浮液於80℃下攪拌直至得到澄清溶液，隨後添加MeONa (372.6 mg, 6.9 mmol)並將混合物攪拌30 min。將溶液濃縮至乾燥並將殘餘物與MeCN (30 mL)共蒸發。將殘餘固體懸浮於MeCN (30 mL)中並添加4-異氰酸基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(1.4 g, 7.2 mmol)。將混合物溶液於室溫下攪拌16 hr並過濾。將濾餅與PE/EA (5/1, 40 mL)一起研磨，從而產生白色固體狀(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(2.4 g，產率：80%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 4.50 (d,J = 12.0 Hz, 1H), 4.21-4.08 (m, 3H), 3.95 (s, 1H), 3.34 (重疊, 3H), 2.76 (t,J = 6.8 Hz, 4H), 2.67 (t,J = 6.8 Hz, 4H), 1.94-1.88 (m, 4H)。MS: m/z 433.1 (M+H+ )。實例 26 下文顯示(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 於0℃下向(R )-3-氯丙烷-1,2-二醇(61.0 g, 552.0 mmol)於吡啶(450 mL)中之溶液中逐份添加TsCl (105.2 g, 552.0 mmol)。於室溫下攪拌1 hr後，將反應用H2 O (10 mL)淬滅並濃縮。將殘餘物倒入aq.HCl (2 N, 200 mL)並用DCM (300 mL x3)萃取。將合併之有機層用飽和NaHCO3 (300 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色油狀(R )-4-甲苯磺酸3-氯-2-羥丙基酯(121.8 g, 粗製，產率：76%)。步驟 2 將(R )-4-甲苯磺酸3-氯-2-羥丙基酯(121.8 g, 461.4 mmol)、CH3 I (43 mL, 690.4 mmol)及Ag2 O (128.0 g, 551.7 mmol)於DCM (1 L)中之混合物於45℃下回流24 hr。添加另一份CH3 I (28.7 mL, 460.8 mmol)並將反應再回流24 hr。藉由過濾移除Ag2 O並濃縮濾液，藉由矽膠管柱(PE/EA = 8/1)純化，從而產生黃色油狀(R )-4-甲苯磺酸3-氯-2-甲氧基丙基酯(77.0 g，產率：60%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.79 (d,J = 8.1 Hz, 2H), 7.35 (d,J = 8.1 Hz, 2H), 4.15-4.08 (m, 2H), 3.64-3.50 (m, 3H), 3.38 (s, 3H), 2.44 (s, 3H)。步驟 3~4 將(R )-4-甲苯磺酸3-氯-2-甲氧基丙基酯(26.2 g, 94.2 mmol)、1-乙醯基-1,2-二氫-吡唑-3-酮(11.9 g, 94.2 mmol)及K2 CO3 (39.0 g, 282.6 mmol)於DMF (350 mL)中之混合物於50℃下攪拌16 hr。添加H2 O (35 mL)並將反應物於130℃下再攪拌3 hr。藉由過濾移除K2 CO3 並濃縮濾液。藉由矽膠管柱(PE/EA = 2/1)純化殘餘物，從而產生白色固體狀(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(13.8 g，含有一些DMF及未知副產物，產率：95%)。1 H NMR (400 MHz, CDCl3 ): δ = 7.33 (d,J = 2.0 Hz, 1H), 5.50 (d,J = 2.4 Hz, 1H), 4.40-4.34 (m, 1H), 4.32-4.23 (m, 2H), 4.17 (dd,J = 11.6, 1.6 Hz, 1H), 3.92-3.89 (m, 1H), 3.48 (s, 3H)。步驟 5 於0℃下向(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(13.8 g, 89.6 mmol)於DCM (150 mL)中之溶液中逐滴添加ClSO3 H (13.1 mL, 197.1 mmol)。於室溫下攪拌16 hr後，於0℃下逐滴添加吡啶(15.8 mL, 197.1 mmol)且隨後於0℃下逐份添加PCl5 (41.0 g, 197.1 mmol)。將反應混合物於室溫下攪拌1 hr，傾倒至冰水(200 mL)上並用EA (100 mL x3)萃取。將合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色固體狀(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯(16.7 g, 粗製，產率：74%)。步驟 6 向(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯(16.7 g, 66.3 mmol)於THF (100 mL)中之溶液中添加NH3 .H2 O (42 mL)。於60℃下攪拌2 hr後，將反應混合物濃縮至約20 mL。將殘餘懸浮液用aq.HCl (1 N)酸化至pH = 3並過濾。將濾餅用H2 O (50 mL)洗滌並與MeOH (20 mL)一起研磨，從而產生白色固體狀(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(10.7 g，產率：69%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.49 (s, 1H), 7.12 (s, 2H), 4.59 (td,J = 11.6, 2.4 Hz, 1H), 4.32 (d,J = 12.0 Hz, 1H), 4.27-4.17 (m, 2H), 4.04-4.02 (m, 1H), 3.35 (s, 3H)。步驟 7 (R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺係如先前實例中步驟 8 中所述合成，以產生白色固體狀期望產物(2.4 g，產率：80%)。實例 27 下文顯示(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之替代合成。 步驟 1 於-78℃下在N2 下向(R )-3-溴-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.0 g, 4.3 mmol)於無水THF (10mL)中之溶液中緩慢添加己烷中之n-BuLi (2.5 M, 2.1 mL, 5.2 mmol)。在冷卻下攪拌1 hr後，於此溫度下緩慢添加(BnS)2 (1.6 g，6.5 mmol)。移除冷卻浴並將反應於室溫下攪拌過夜。將反應用飽和NH4 Cl溶液(5 mL)淬滅並分配在水(20mL)與EA (20 mL)之間。將有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生黃色油狀(R )-3-(苄基硫基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(760 mg，產率：63%)。MS: m/z 277.4 (M+H+ )。步驟 2 於0℃下在N2 下向(R )-3-(苄基硫基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(750 mg, 2.7 mmol)於AcOH/H2 O (3 mL/1 mL)中之溶液中，取NCS (1.5 g, 10.9 mmol)分成兩份添加。隨後將反應於室溫下攪拌1 hr。將反應物分配在EA (20 mL)與水(20 mL)之間。將有機層用飽和NaHCO3 (20 mL)及鹽水(20 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮，從而產生黃色油狀粗製(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯，其未經任何純化即用於下一步驟。步驟 3 (R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 C 中合成，從而產生白色固體狀期望產物(280 mg，產率：經2個步驟44%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.48 (s, 1H), 7.11 (s, 2H), 4.61-4.56 (m, 1H), 4.34 (d,J = 11.6 Hz, 1H), 4.26-4.16 (m, 2H), 4.03 (d,J = 1.2 Hz, 1H), 3.35 (s, 3H)。MS: m/z 233.8 (M+H+ )。實例 28 下文顯示外消旋 - N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 在N2 下在冰冷卻下向2-甲基-丙烷-1,3-二醇(1 g, 11.1 mmol)及TEA (4.5 g, 44.4 mmol)於THF (30 mL)中之溶液中緩慢添加MsCl (2.8 g, 24.4 mmol)。將反應於室溫下攪拌1 hr並過濾。濃縮濾液以產生無色油。將此油1,2-二氫-吡唑-3-酮(993 mg, 11.1 mmol)及K2 CO3 (6.1 g, 44.4 mmol)於DMF (40 mL)中之混合物加熱至80℃並保持12 hr。將反應物冷卻並分配在EA (100 mL)與水(200 mL)之間並分離各層。將有機層用水(80 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 2/1)純化殘餘物，從而產生白色固體狀外消旋 - 6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(500 mg，產率：33%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.31 (s, 1H), 5.47 (s, 1H), 4.27-4.23 (m, 2H), 3.87-3.68 (m, 2H), 2.47-2.45 (m,1H), 1.23-1.09 (m,3H)。MS: m/z 139.0 (M+H+ )。步驟 2~3 將外消旋 - 6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(500 mg, 3.6 mmol)於氯磺酸(5 mL)中之溶液於80℃下攪拌過夜。將反應物溶解於EA (60 mL)中並緩慢添加至水(100 mL)中。將有機層用鹽水(60 mL)洗滌，經Na2 SO4 乾燥並濃縮。將殘餘物溶解於THF (15 mL)中並添加氨(5 mL)。將混合物於60℃下攪拌1 hr。濃縮反應，用1 N HCl酸化並藉由反相HPLC (MeCN/H2 O)純化，從而產生白色固體狀外消旋 - 6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(450 mg，產率：經2個步驟58%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.46 (s, 1H), 7.11 (brs, 2H), 4.43-4.38 (m, 1H), 4.21-4.15 (m, 1H), 4.06-3.99 (m, 1H), 3.76-3.69 (m, 1H), 2.42-2.34 (m,1H), 1.02-1.00 (m,3H)。步驟 4 外消旋 - N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(29.7 mg，產率：18%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.49 (s, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.48-4.45 (m, 1H), 4.44-4.18 (m, 1H), 4.08 (t,J = 11.4 Hz, 1H), 3.77-3.72 (m, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 2.40 (重疊, 1H), 1.98-1.91 (m, 4H), 1.01 (d,J = 6.4 Hz, 3H)。MS: m/z 417.0 (M+H+ )。實例 29 下文顯示(S )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺及(R )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 藉由手性prep-HPLC拆分外消旋 - 6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(350 mg)，從而產生(S )-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(242 mg，呈二乙胺鹽形式)及(R )-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(240 mg，呈二乙胺鹽形式)。步驟 2 (R )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 A 中合成，從而產生白色固體狀期望產物(112 mg，產率：37%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (brs, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.48-4.45 (m, 1H), 4.44-4.18 (m, 1H), 4.08 (t,J = 11.4 Hz, 1H), 3.77-3.72 (m, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 2.40 (重疊, 1H), 1.98-1.91 (m, 4H), 1.00 (d,J = 6.4 Hz, 3H)。MS: m/z 417.1 (M+H+ )。 (S )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用相同程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.48-4.44 (m, 1H), 4.22-4.18 (m, 1H), 4.11-4.06 (m, 1H), 3.77-3.72 (m, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.42-2.38 (m, 1H), 1.98-1.92 (m, 4H), 1.00 (d,J = 6.8 Hz, 3H)。MS: m/z 417.1 (M+H+ )。實例 30 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-5',7'-二氫螺[環丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺醯胺之合成。 步驟 1 在N2 下在冰冷卻下向(1-羥基甲基-環丙基)-甲醇(1.53 g, 15 mmol)及TEA (6.1 g, 60 mmol)於THF (45 mL)中之溶液中緩慢添加MsCl (3.8 g, 33 mmol)。於室溫下攪拌1 hr後，將反應物分配在EA (500 mL)與水(100 mL)之間。將有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生無色油。將此油1,2-二氫-吡唑-3-酮(1.3 g, 15 mmol)及K2 CO3 (8.3 g, 60 mmol)於DMF (60 mL)中之混合物加熱至80℃過夜。將反應物冷卻並分配在EA (120 mL)與水(300 mL)之間。將有機層用水(100 mL)及鹽水(80 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生白色固體狀5',7'-二氫螺[環丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪] (380 mg，產率：17%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (d,J = 1.8 Hz, 1H), 5.52 (d,J = 1.8 Hz, 1H), 3.99 (s, 4H), 0.81-0.49 (m, 4H)。MS: m/z 151.0 (M+H+ )。步驟 2 向5',7'-二氫螺[環丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪] (380 mg, 5.3 mmol)於MeCN (15 mL)中之溶液中逐份添加NBS (960 mg, 5 mmol)。於室溫下攪拌1 hr後，將反應物分配在EA (60 mL)與水(60 mL)之間。將有機層用鹽水(60 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 2/1)將殘餘物純化成黃色固體狀3'-溴-5',7'-二氫螺[環丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪] (380 mg，產率：66%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s, 1H), 4.07 (s, 2H), 3.98 (s, 2H), 0.86-0.81 (m, 4H)。MS: m/z 230.9 (M+H+ )。步驟 3 5',7'-二氫螺[環丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經任何純化即用於下一步驟。步驟 4 5',7'-二氫螺[環丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺醯胺係如製法 C 中合成，從而產生白色固體狀期望產物(105 mg，產率：經2個步驟27%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.49 (s, 1H), 7.12 (brs, 2H), 4.20 (s,2H), 4.00 (s,2H), 0.78 (s, 4H)。步驟 5 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-5',7'-二氫螺[環丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(54 mg，產率：34%).1 H NMR (400 MHz, DMSO-d 6 ): δ =10.53 (s, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 6.94 (s, 1H), 4.25 (s, 2H), 4.01 (s, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.93 (m, 4H), 0.78 (s, 4H)。MS: m/z 429.0 (M+H+ )。實例 31 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-甲苯磺醯基-5',7'-二氫螺[氮雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺醯胺之合成。 步驟 1 於0℃下向[3-溴甲基-1-(甲苯-4-磺醯基)-氮雜環丁-3-基]-甲醇(4 g, 12 mmol)於DCM (60 mL)中之溶液中添加CBr4 (6.4 g, 19.2 mmol)及PPh3 (5.2 g, 19.2 mmol)。於室溫下攪拌16 hr後，將反應物分配在DCM (200 mL)與H2 O (200 mL)之間。用DCM (200 mL)萃取水層。將合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 5/1)純化殘餘物，從而產生黃色固體狀3,3-雙-溴甲基-1-(甲苯-4-磺醯基)-氮雜環丁烷(3.8 g，產率：79%)。MS: m/z 395.9 (M+H+ )。步驟 2 向3,3-雙-溴甲基-1-(甲苯-4-磺醯基)-氮雜環丁烷(4.2 g, 10.6 mmol)及1,2-二氫-吡唑-3-酮(0.89 g, 10.6 mmol)於DMF (50 mL)中之溶液中添加K2 CO3 (3.7 g, 26.5 mmol)。於130℃下攪拌16 hr後，將反應冷卻並利用添加EA (100 mL)及水(100 mL)淬滅。分離有機層。用EA (100 mL)萃取水層。合併有機層，用鹽水(80 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生白色固體狀1-甲苯磺醯基-5',7'-二氫螺[氮雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪] (1.4 g，產率：42%)。MS: m/z 320 (M+H+ )。步驟 3 於0℃下向1-甲苯磺醯基-5',7'-二氫螺[氮雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪] (1 g, 0.33 mmol)於MeCN (10 mL)中之溶液中逐份添加NBS (0.64 g, 3.6 mmol)並將反應於室溫下攪拌2 hr。過濾混合物並藉由反相HPLC (5% - 95% H2 O中之MeCN)純化濾液，從而產生黃色固體狀3'-溴-1-甲苯磺醯基-5',7'-二氫螺[氮雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪] (1.16 g，產率：83%)。MS: m/z 398 (M+H+ )。步驟 4 1-甲苯磺醯基-5',7'-二氫螺[氮雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物。 1-甲苯磺醯基-5',7'-二氫螺[氮雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺醯胺係如製法 C 中合成，從而產生淺黃色固體狀期望產物(140 mg，產率：32%)。MS: m/z 399.1 (M+H+ )。步驟 5 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-甲苯磺醯基-5',7'-二氫螺[氮雜環丁烷-3,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺醯胺係使用製法 A 合成且藉由prep HPLC進一步純化以遞送白色固體狀期望產物(24 mg，產率：22%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.52 (s, 1H), 7.90 (s, 1H), 7.74 (d,J = 8.0 Hz, 2H), 7.62 (s, 1H), 7.53 (d,J = 8.0 Hz, 2H), 6.94 (s, 1H), 4.24 (s, 2H), 4.00 (s, 2H), 3.68 (s, 4H), 2.80 (t,J = 7.2 Hz, 4H), 2.55 (t,J = 6.8 Hz, 4H), 2.46 (s, 3H), 1.91-1.98 (m, 4H)。MS: m/z 598.2 (M+H+ )。實例 32 下文顯示6-胺基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向2-胺基丙烷-1,3-二醇(5.0 g, 54.9 mmol)及TEA (11.1 g, 109.9 mmol)於DCM (40 mL)中之溶液中添加Boc2 O (14.4 g, 65.9 mmol)並將反應於室溫下攪拌2 hr。將反應物分配在水(80 mL)與EA (80 mL)之間。將有機層用鹽水(80 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生白色固體狀粗製(1,3-二羥基丙-2-基)胺基甲酸第三丁基酯，其未經任何純化即用於下一步驟。步驟 2 於0℃下向(1,3-二羥基丙-2-基)胺基甲酸第三丁基酯(粗製，約21.0 mmol)及TEA (8.5 g, 84.0 mmol)於無水THF (30 mL)中之溶液中添加MsCl (5.3 g, 46.0 mmol)。於室溫下攪拌2 hr後，過濾反應。將濾液濃縮至乾燥。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生白色固體狀二甲烷磺酸2-((第三丁氧基羰基)胺基)丙烷-1,3-二基酯(3.9 g，產率：53%)。1 H NMR (300 MHz, CDCl3 ): δ = 5.11 (d,J = 7.5 Hz, 1H), 4.36-4.22 (m, 5H), 3.07 (s, 6H), 1.44 (s, 9H)。步驟 3 將二甲烷磺酸2-((第三丁氧基羰基)胺基)丙烷-1,3-二基酯(3.9 g, 11.2 mmol)、1,2-二氫-吡唑-3-酮(945 mg, 11.2 mmol)及K2 CO3 (5.4 g, 39.3 mmol)於DMF (30 mL)中之混合物加熱至80℃並保持12 hr。將反應物冷卻並分配在EA (150 mL)與水(200 mL)之間。將有機層用水(80 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生白色固體狀(6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(975 mg，產率：13%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.37 (d,J = 1.2 Hz, 1H), 5.55 (d,J = 1.5 Hz, 1H), 5.14-5.04 (m, 1H), 4.43-4.12 (m, 5H), 1.46 (s,9H)。MS: m/z 240.1 (M+H+ )。步驟 4 於0℃下在N2 下向(6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(610 mg, 2.6 mmol)於MeCN中之溶液中， 取NBS (454 mg, 2.6 mmol)分成兩份添加。隨後將反應於室溫下攪拌1 hr。將反應物分配在EA (20 mL)與水(20 mL)之間。將有機層用水(20 mL)及鹽水(20 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生白色固體狀(3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(640 mg，產率：79%)。MS: m/z 318.0 (M+H+ )。步驟 5 6-((第三丁氧基羰基)胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色凝膠狀產物，其未經任何純化即用於下一步驟。步驟 6 將6-((第三丁氧基羰基)胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯(粗製，約1.9 mmol)、NH4 OH (20 mL)及THF (20 mL)中之混合物於60℃下攪拌過夜。在減壓下濃縮反應直至剩餘10 mL液體。將剩餘溶液用1 N HCl酸化至pH = 5並用EA (20 mL x2)萃取。合併有機層，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(DCM/MeOH = 40/1)純化殘餘物，從而產生黃色半固體狀(3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(80 mg，產率：經2個步驟13%)。MS: m/z 317.0 (M-H+ )。步驟 7 (3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯係使用製法 A 合成以遞送白色固體狀期望產物(28 mg，產率：22%)。步驟 8 向(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(28 mg, 0.05 mmol)於DCM (5 mL)中之溶液中添加TFA (5 mL)並將混合物於室溫下攪拌20 min。將反應物濃縮至乾燥並將殘餘物與EA一起研磨，從而產生白色固體狀6-胺基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之TFA鹽(5.4 mg，產率：23%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.15 (brs, 1H), 7.54 (s, 1H), 6.88 (s, 1H), 4.32-4.30 (m, 1H), 4.21-4.16 (m, 1H), 4.11-4.01 (m, 1H), 3.81-3.75 (m, 1H), 3.47 (重疊, 1H), 2.77 (t,J = 7.2 Hz, 4H), 2.67-2.62 (m, 4H), 1.97-1.92 (m, 4H)。MS: m/z 418.2 (M+H+ )。實例 33 下文顯示((6-(((第三丁氧基羰基)胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉之合成。 步驟 1 將1,2-二氫-吡唑-3-酮(10.42 g, 0.124 mol)及K2 CO3 (42.8 g, 0.31 mol)於DMF (700 mL)之混合物加熱至100℃。添加3-氯-2-氯甲基-丙烯(15.5 g, 0.124 mol)並將混合物於100℃下攪拌16 hr。在真空中移除溶劑.將殘餘物分配在EA (200 mL)與H2 O (500 mL)之間。用EA (200 mL)萃取水層。將合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生黃色油狀6-亞甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.7 g，產率：10%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.34 (s, 1H), 5.51 (s, 1H), 5.39 (s, 2H), 4.80 (s, 2H), 4.63 (s, 2H)。MS: m/z 137.1 (M+H+ )。步驟 2 於0℃下向6-亞甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.7 g, 12.5 mmol)於THF (20 mL)中之溶液中添加BH3 /Me2 S(10 M, 5 mL, 50 mmol)。於室溫下攪拌16 hr後，向反應中緩慢添加NaOH溶液(3 M, 50 mL, 150 mmol)及H2 O2 (30%, 5.7 g, 50 mmol)。於80℃下攪拌2 hr後，冷卻反應物。向反應中添加飽和Na2 SO3 水溶液(50 mL)。於室溫下攪拌0.5 hr後，將所得混合物用EA (100 mL x3)萃取。將合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色油狀(6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)-甲醇(1.3 g，產率：68%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.31 (d,J = 1.8 Hz, 1H), 5.49 (d,J = 1.8 Hz, 1H), 4.37 (dd,J = 11.4, 3 Hz,1H), 4.28-4.12 (m,2H), 4.07-4.00 (m,1H), 3.77 (d,J = 6.6 Hz, 2H), 2.58-2.50 (m, 1H)。步驟 3 於室溫下向(6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)-甲醇(2.05 g, 13.3 mmol)於THF (30 mL)中之溶液中添加DPPA (7.3 g, 26.6 mmol)及DBU (6.1 g, 39.9 mmol)。將懸浮液於60℃下攪拌16 hr。利用添加EA (100 mL)及水(100 mL)淬滅反應。分離有機層。用EA (100 mL)萃取水層。將有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。藉由矽膠管柱(PE/EA = 2/1)純化殘餘物，從而產生黃色油狀6-疊氮基甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.24 g，產率：62%)。MS: m/z 180.3 (M+H+ )。步驟 4 向6-疊氮基甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.24 g, 16.9 mmol)於MeOH (20 mL)中之溶液中添加Boc2 O (3 g, 13.8 mmol)及Pd/C (5%, 0.2 g)。將混合物在H2 (氣球氣氛)下於室溫下攪拌16 hr。過濾反應並濃縮濾液，從而產生粗產物，其不經進一步純化即直接用於下一步驟。MS: m/z 254.0 (M+H+ )。步驟 5 於0℃下向((6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)胺基甲酸第三丁基酯(粗製, 6.9 mmol)於MeCN (20 mL)中之溶液中逐份添加NBS (1.3 g, 24.7 mmol)並將反應於室溫下攪拌2 hr。將混合物過濾並藉由反相HPLC (5% - 95% H2 O中之MeCN)純化，從而產生黃色固體狀((3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)胺基甲酸第三丁基酯(1.62 g，產率：71%)。MS: m/z 331.9 (M+H+ )。步驟 6 6-(((第三丁氧基羰基)胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經任何純化即用於下一步驟。步驟 7 ((3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)胺基甲酸第三丁基酯係如製法 C 中合成，從而產生淺黃色固體狀期望產物(80 mg，產率：經2個步驟33%)。MS: m/z 333.4 (M+H+ )。步驟 8 ((6-(((第三丁氧基羰基)胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺係如製法 D 中合成，從而產生白色固體狀期望產物(27 mg，產率：21%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.35 (s, 1H), 7.31 (s, 1H), 7.11 (s, 1H), 6.75 (s, 1H), 4.31 (d,J = 5.6 Hz, 1H), 4.10-3.98 (m, 2H), 3.78 (dd,J = 10.0, 2.0 Hz, 1H), 3.07-3.04 (m, 2H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.40-2.3 (m, 1H), 1.93-1.86 (m, 4H), 1.39 (s, 9H)。MS: m/z 532.2 (M+H+ )。實例 34 下文顯示外消旋 - N-((3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)乙醯胺之合成。 步驟 1 向外消旋 - ((6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)胺基甲酸第三丁基酯(粗製，約1.05 mmol)於DCM (3 mL)中之溶液中添加TFA (1 mL)。將溶液於室溫下攪拌2 hr後，濃縮溶液並用Ac2 O (3 mL)溶解。於回流下攪拌3 hr後，利用添加EA (20 mL)及水(10 mL)淬滅反應溶液。分離有機層。用EA (10 mL)萃取水層。合併有機層並用鹽水(10 mL)洗滌且經Na2 SO4 乾燥。在真空中濃縮溶液。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生黃色油狀外消旋 - N-乙醯基-N-((6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)乙醯胺(90 mg，產率：31%)。MS: m/z 238.4 (M+H+ )。步驟 2 於0℃下向外消旋 - N-乙醯基-N-((6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)乙醯胺(90 mg, 0.38 mmol)於DCM (2 mL)中之溶液中逐滴添加ClSO3 H (0.075 mL, 1.14 mmol)。於室溫下攪拌16 hr後，於0℃下向反應中逐滴添加吡啶(0.092 mL, 1.14 mmol)，之後逐份添加PCl5 (237 mg, 1.14 mmol)。將反應混合物於室溫下攪拌1 hr，倒入冰水(2 mL)並用EA (10 mL x3)萃取。將合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生粗產物，其不經進一步純化即直接用於下一步驟。步驟 3 向外消旋 - 6-((N-乙醯基乙醯胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯(粗製，約0.387 mmol)於THF (3 mL)中之溶液中添加NH3 .H2 O (3 mL)。於60℃下攪拌2 hr後，將反應混合物濃縮至約1 mL。將殘餘懸浮液用aq.HCl (1 N)酸化至pH = 3並過濾。藉由反相HPLC (MeCN/H2 O)純化濾液，從而產生白色固體狀外消旋 - N-((3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)乙醯胺(67 mg，產率：64%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.02 (brs, 1H), 7.37 (s, 1H), 6.65 (brs, 2H), 4.40-4.30 (m, 1H), 4.17-4.04 (m, 2H), 3.85-3.73 (m, 1H), 3.10-3.00 (m, 2H), 2.50 (重疊, 1H), 1.76 (s, 3H)。步驟 4 外消旋 - N-((3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)乙醯胺係如製法 D 中合成，從而產生白色固體狀期望產物(34 mg，產率：48%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (s, 1H), 8.07 (t,J = 6 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.48 (d,J = 8.8 Hz, 1H), 4.26-4.14 (m, 2H), 3.93-3.85 (m, 1H), 3.23-3.08 (m, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.59 (t,J = 6.8 Hz, 4H), 2.50 (重疊, 1H), 2.10-1.90 (m, 4H), 1.83 (s, 3H)。MS: m/z 474.2 (M+H+ )。實例 35 下文顯示外消旋 - 6-((二甲基胺基)甲基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於0℃下向外消旋 - ((3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)胺基甲酸第三丁基酯(110 mg, 0.33 mmol)於MeOH (2 mL)中之溶液中添加HCl/二噁烷(4 M, 1 mL, 4 mmol)。於室溫下攪拌2 hr後，濃縮溶液，從而產生粗製外消旋 - 6-(胺基甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺鹽酸鹽，其不經進一步純化即直接用於下一步驟。步驟 2 向外消旋 - 6-(胺基甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺鹽酸鹽(粗製, 0.33 mmol)於MeOH (2 mL)中之溶液中添加HCHO (1.5 mL)及NaCNBH3 (20.8 mg, 0.33 mmol)。於室溫下攪拌3 hr後，過濾反應並藉由反相HPLC (MeCN/H2 O)純化濾液，從而產生白色固體狀外消旋 - 6-((二甲基胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(50 mg，產率：59%)。MS: m/z 261.1 (M+H+ )。步驟 3 外消旋 - 6-((二甲基胺基)甲基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 D 中合成，從而產生白色固體狀期望產物(27 mg，產率：21%)。1 H NMR (400 MHz, DMSO-d 6 + CD3 OD): δ = 7.37 (s, 1H), 7.32 (s, 1H), 6.75 (s, 1H), 4.37 (dd,J = 6.8, 2.8 Hz, 1H), 4.10-4.00 (m, 2H), 3.80-3.75 (m, 1H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.47-2.43 (m, 1H), 2.23 (d,J = 7.2 Hz, 2H), 2.14 (s, 6H), 1.95-1.85 (m, 4H)。MS: m/z 460.1 (M+H+ )。實例 36 下文顯示外消旋 - N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-(甲氧基甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於0℃下向外消旋 - (6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)-甲醇(0.6 g, 3.9 mmol)於THF (10 mL)中之溶液中添加NaH (187 mg, 4.7 mmol)，之後添加MeI (667 mg, 4.7 mmol)。攪拌過夜後，利用添加EA (20 mL)及水(20 mL)淬滅反應。分離有機層。用EA (20 mL)萃取水層。合併有機層，用鹽水(30 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生黃色固體狀外消旋 - 6-甲氧基甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(270 mg，產率：41%)。MS: m/z 169.3 (M+H+ )。步驟 2 於0℃下向6-甲氧基甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(230 mg, 1.37 mmol)於MeCN (5 mL)中之溶液中逐份添加NBS (256 mg, 1.44 mmol)並將反應於室溫下攪拌2 hr。過濾混合物並藉由反相HPLC (5% - 95% H2 O中之MeCN)純化濾液，從而產生黃色油狀3-溴-6-(甲氧基甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(220 mg，產率：65%)。MS: m/z 247.3 (M+H+ )。步驟 3 6-(甲氧基甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經任何純化即用於下一步驟。步驟 4 6-(甲氧基甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 C 中合成，從而產生淺黃色固體狀期望產物(25 mg，產率：經2個步驟13%)。步驟 5 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-(甲氧基甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 D 中合成，從而產生白色固體狀期望產物(9 mg，產率：20%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.46 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.51 (dd,J = 10.8, 2.8 Hz, 1H), 4.29 (dd,J = 11.2, 7.2 Hz, 1H), 4.51 (dd,J = 12.4, 5.2 Hz, 1H), 4.51 (dd,J = 12.4, 7.2 Hz, 1H), 3.43 (d,J = 3.6 Hz, 2H), 3.25 (s, 3H), 2.79 (t,J = 7.2 Hz, 4H), 2.61-2.58 (m, 5H), 1.99-1.92 (m, 4H)。MS: m/z 446.8 (M+H+ )。實例 37 下文顯示外消旋 - 6-乙氧基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向外消旋 - 3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(700 mg, 3.2 mmol)於DMF (10 mL)中之溶液中添加NaH (60%於礦物油中, 192 mg, 4.8 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加碘乙烷(549 mg, 3.5 mmol)並將混合物於室溫下攪拌2 hr。將反應混合物倒入水(60 mL)中並用EA (50 mL)萃取。將有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生白色固體狀外消旋 - 3-溴-6-乙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(640 mg，產率：81%)。 MS: m/z 248.9 (M+H+ )。步驟 2 6-乙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經任何純化即用於下一步驟。步驟 3 將外消旋 - 6-乙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯(粗製)及NH3 .H2 O (8.4 mL)於THF (8.4 mL)中之溶液於60℃下攪拌16 hr。將混合物在真空中濃縮。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生白色固體狀外消旋 - 6-乙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(222.0 mg，產率：35%)。 MS: m/z 247.9 (M+H+ )。步驟 4 - 製法 F 向外消旋 - 6-乙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(116 mg, 0.47 mmol)於THF (8.0 mL)中之溶液中添加MeONa (28 mg, 0.52 mmol)並將混合物於室溫下攪拌20 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(81 mg, 0.47 mmol)及TEA (142 mg, 1.4 mmol)於THF (10 mL)中之溶液中一次性添加三光氣(56.0 mg, 0.19 mmol)並將混合物於室溫下在N2 下攪拌20 min。隨後過濾反應混合物。向上述鈉鹽懸浮液中添加濾液並將混合物於室溫下攪拌20 min。其後，將反應溶液分配在EA (60 mL)與水(60 mL)之間。將水相用濃HCl酸化至pH = 5並用EA (60 mL)萃取。將有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮，直至出現白色固體。藉由過濾收集所形成固體並乾燥，從而產生白色固體狀外消旋 - 6-乙氧基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(68 mg，產率：32%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.58 (d,J = 11.6 Hz, 1H), 4.36 (d,J = 11.6 Hz, 1H), 4.27-4.24 (m, 1H), 4.18-4.15 (m, 2H), 3.61-3.56 (m, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.91 (m, 4H), 1.09 (t,J = 7.2 Hz, 3H)。MS: m/z 447.0 (M+H+ )。實例 38 下文顯示(R )-6-乙氧基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺及(S )-6-乙氧基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 藉由手性prep-HPLC拆分外消旋 - 6-乙氧基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(222 mg)，從而產生白色固體狀(R )-6-乙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(20 mg)及白色固體狀(S )-6-乙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(20 mg)。步驟 2 (R )-6-乙氧基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 F 中所述合成以遞送白色固體狀期望產物(5.0 mg，產率：14%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 10.47 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.58 (d,J = 10.0 Hz, 1H), 4.36 (d,J = 11.2 Hz, 1H), 4.27-4.24 (m, 1H), 4.18-4.15 (m, 2H), 3.59 (q,J = 7.2 Hz, 2H), 2.79 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.91 (m, 4H), 1.09 (t,J = 6.8 Hz, 3H)。MS: m/z 447.1 (M+H+ )。 (S )-6-乙氧基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用相同程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.59 (d,J = 11.6 Hz, 1H), 4.37 (d,J = 11.6 Hz, 1H), 4.27-4.23 (m, 1H), 4.17-4.15 (m, 2H), 3.53 (q,J = 7.2 Hz, 2H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H), 1.08 (t,J = 7.2 Hz, 3H)。MS: m/z 447.1 (M+H+ )。實例 39 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-異丙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向丙二酸二甲基酯(5.0 g, 38.0 mmol)及TEA (7.7 g, 76.0 mmol)於MeCN (80 mL)中之溶液中添加4-乙醯胺基苯磺醯基疊氮化物(9.1 g, 38.0 mmol)並將反應於室溫下攪拌16 hr。過濾反應並將濾液分配在水(80 mL)與EA (80 mL)之間。將有機層用鹽水(80 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 10/1)純化殘餘物，從而產生黃色油狀2-二偶氮丙二酸二甲基酯(3.9 g，產率：53%)。步驟 2 向2-二偶氮丙二酸二甲基酯(3.4 g, 21.5 mmol)及Rh2 (Ac)4 (36 mg, 0.2 mmol)於DCM (10 mL)中之溶液中添加i-PrOH (132.0 g, 0.2 mol)並將反應於70℃下攪拌4 hr。將反應物濃縮至乾燥。藉由矽膠管柱(PE/EA = 10/1)純化殘餘物，從而產生無色油狀2-異丙氧基丙二酸二甲基酯(3.7 g，產率：90%)。1 H NMR (300 MHz, CDCl3 ): δ = 4.60 (s, 1H), 3.81-3.74 (m, 7H), 1.26 (d,J = 6.0 Hz, 6H)。步驟 3 於0℃下向2-異丙氧基丙二酸二甲基酯(3.7 g, 19.4 mmol)於無水THF (30 mL)中之溶液中添加LiBH4 (2 M於THF中, 19.4 mL, 38.7 mol)並將反應於室溫下攪拌2 hr。將反應由H2 O (20 mL)淬滅並將混合物經MgSO4 乾燥。過濾反應並將濾液濃縮至乾燥，從而產生無色油狀2-異丙氧基丙烷-1,3-二醇(2.5 g，產率：96%)。1 H NMR (300 MHz, CDCl3 ): δ = 3.72-3.50 (m, 6H), 1.26 (t,J = 5.4 Hz, 2H), 1.22 (d,J = 6.0 Hz, 6H)。步驟 4 於0℃下向2-異丙氧基丙烷-1,3-二醇(2.5 g, 18.7 mmol)及TEA (5.7 g, 56.0 mmol)於無水THF (30 mL)中之溶液中添加MsCl (4.7 g, 41.0 mmol)。於室溫下攪拌2 hr後，過濾反應。將濾液濃縮至乾燥，從而產生白色固體狀粗製二甲烷磺酸2-異丙氧基丙烷-1,3-二基酯，其未經任何純化即用於下一步驟。步驟 5 將二甲烷磺酸2-異丙氧基丙烷-1,3-二基酯(粗製，約18.7 mmol)、1,2-二氫-吡唑-3-酮(1.6 g, 18.7 mmol)及K2 CO3 (7.7 g, 56.0 mmol)於DMF (40 mL)中之混合物加熱至100℃並保持16 hr。將反應冷卻並分配在EA (150 mL)與水(200 mL)之間並分離各層。將有機層用水(80 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/2)純化殘餘物，從而產生白色固體狀6-異丙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(2.1 g，產率：88%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s,1H), 5.49 (s,1H), 4.31-3.84 (m, 5H), 3.84-3.80 (m, 1H), 1.22-118 (m, 6H)。MS: m/z 183.3 (M+H+ )。步驟 6 於0℃下在N2 下向6-異丙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.0 g, 7.8 mmol)於MeCN中之溶液中，取NBS (1.5 g, 8.6 mmol)分成兩份添加。隨後將反應於室溫下攪拌2 hr。將反應物分配在EA (40 mL)與水(40 mL)之間，。將有機層用水(40 mL)及鹽水(40 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 2/1)純化殘餘物，從而產生黃色固體狀3-溴-6-異丙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(1.2 g，產率：75%)。MS: m/z 261.2 (M+H+ )。步驟 7 6-異丙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色凝膠狀產物，其未經任何純化即用於下一步驟。 6-異丙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 C 中合成，從而產生黃色固體狀期望產物(110 mg，產率：經2個步驟22%)。MS: m/z 262.3 (M+H+ )。步驟 8 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-異丙氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(18 mg，產率：10%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (brs, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.49-4.46 (m, 1H), 4.37 (d,J = 12.0 Hz, 1H), 4.28-4.24 (m, 2H), 4.09-4.06 (m, 1H), 3.87-3.81 (m, 1H), 2.77 (t,J = 8.0 Hz, 4H), 2.61 (重疊, 4H), 1.97-1.91 (m, 4H), 1.09-1.05 (m, 6H)。MS: m/z 461.1 (M+H+ )。實例 40 下文顯示外消旋 - ((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 向2-胺基丙烷-1,3-二醇(10.0 g, 0.1 mol)於EtOH (100 mL)中之溶液中添加二碳酸二第三丁基酯(24.0 g, 0.1 mol)。將反應於室溫下攪拌16 hr。將反應溶液在真空中濃縮至乾燥，從而產生白色固體狀(1,3-二羥基丙-2-基)胺基甲酸第三丁基酯(21.0 g，產率：100%)。步驟 2 於0℃下向(1,3-二羥基丙-2-基)胺基甲酸第三丁基酯(21.0 g, 0.1 mol)及TEA (23.0 g, 0.2 mol)於無水CH2 Cl2 (200 mL)中之溶液中添加MsCl (26.0 g, 0.2 mol)。於室溫下攪拌2 hr後，過濾反應。將濾液濃縮至乾燥，從而產生白色固體狀粗製二甲烷磺酸2-((第三丁氧基羰基)胺基)丙烷-1,3-二基酯(37.0 g，產率：97%)，其未經任何純化即用於下一步驟。步驟 3 將DMF (300 mL)中之二甲烷磺酸2-((第三丁氧基羰基)胺基)丙烷-1,3-二基酯(37.3 g, 0.11 mol)、1H-吡唑-3(2H)-酮(9.0 g, 0.11 mol)及K2 CO3 (30.0 g, 0.22 mol)於120℃下加熱16 hr。濃縮後，將殘餘物分配在EA (300 mL)與水(500 mL)之間。用EA (300 mL)萃取水層。將合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥，過濾並在真空中濃縮至乾燥，從而產生黃色固體狀外消旋 - (6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(8.8 g，產率：34%)。MS: m/z 240.0 (M+H+ )。步驟 4 於0℃下向外消旋 - (6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(8.8 g, 37.0 mmol)於MeCN (100 mL)中之溶液中逐份添加NBS (6.5 g, 37.0 mmol)並將反應於室溫下攪拌2 hr。濃縮反應混合物。藉由矽膠管柱(PE/EA = 5/1)純化殘餘物，從而產生黃色固體狀外消旋 - (3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(2.5 g，產率：21%)。MS: m/z 319.9 (M+H+ )。步驟 5 向外消旋 - (3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(900 mg, 2.8 mmol)於DMF (10 mL)中之溶液中添加NaH (60%於礦物油中, 226 mg, 5.7 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加碘甲烷(2.0 g, 14.2 mmol)並將混合物於室溫下攪拌2 hr。將反應混合物倒入水(60 mL)中並用EA (50 mL)萃取。將有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生黃色固體狀外消旋 - (3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(550 mg，產率：59%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.36 (s, 1H), 4.6 (br, 1H), 4.38-4.29 (m, 4H), 2.82 (d,J = 3.6 Hz, 3H), 1.50 (s, 9H)。MS: m/z 333.9 (M+H+ )。步驟 6 外消旋 - 6-((第三丁氧基羰基)(甲基)胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經任何純化即用於下一步驟。步驟 7 將外消旋 - 6-((第三丁氧基羰基)(甲基)胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯(粗製)及NH3 .H2 O (3.0 mL)於THF (5.0 mL)中之溶液於60℃下攪拌16 hr。將混合物在真空中濃縮. 藉由矽膠管柱(CH2 Cl2 /MeOH = 25/1)純化殘餘物，從而產生無色油狀甲基(3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(26.0 mg，產率：8%，2個步驟)。1 H NMR (400 MHz, CDCl3 ): δ = 7.64 (s, 1H), 5.14 (br, 2H), 4.68 (br, 1H), 4.53-4.44 (m, 2H), 4.38-4.26 (m, 2H), 2.84 (s, 3H), 1.48 (s, 9H)。MS: m/z 276.9 (M-56+H+ )。步驟 8 (3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯係如製法 D 中合成，從而產生白色固體狀期望產物(40 mg，產率：95%)。MS: m/z 476.0 (M-55- )。步驟 9 向(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(40 mg, 0.08 mmol)於CH2 Cl2 (2 mL)中之溶液中添加TFA (0.6 mL)並將混合物於室溫下攪拌30 min。隨後將混合物在真空中濃縮以移除溶劑。將殘餘物用2 M NaOH溶液處理至pH ＞ 13。藉由反相HPLC (MeCN/H2 O)純化所得溶液，從而產生白色固體狀外消旋 - ((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(25.0 mg, 78%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.33 (s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.25-4.10 (m, 3H), 3.83-3.79 (m, 1H), 3.07 (m, 1H), 2.77-2.73 (m, 4H), 2.67-2.63 (m, 4H), 2.33 (s, 3H), 1.92-1.88 (m, 4H)。MS: m/z 432.1 (M+H+ )。實例 41 下文顯示(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉及(S )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 藉由手性prep-HPLC拆分外消旋 - N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(400 mg, 1.2 mmol)，從而產生白色固體狀(R )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(240 mg，產率：60%)及白色固體狀(S )-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(150 mg，產率：37%)。步驟 2 ： (R )-(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯係如製法 D 中合成，從而產生白色固體狀期望產物(200 mg，產率：52%)。 (S )-(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯係使用相同程序製備。步驟 3 向(R )-(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(250 mg, 0.75 mmol)於CH2 Cl2 (5 mL)中之溶液中添加TFA (2 mL)並將混合物於室溫下攪拌30 min。隨後將混合物在真空中濃縮以移除溶劑。將殘餘物用2 M NaOH溶液處理至pH ＞ 13。藉由反相HPLC (MeCN/H2 O)純化所得溶液，從而產生白色固體狀(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(130 mg, 30%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.50 (s, 1H), 7.38 (s, 1H), 6.8 (s, 1H), 4.28 (dd,J = 10.8 Hz, 2.4Hz, 1H), 4.20-4.10 (m, 2H), 3.85 (dd,J = 11.6 Hz, 4.8Hz, 1H), 3.14-3.06 (m, 1H), 2.76 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.33 (s, 3H), 1.97-1.86 (m, 4H)。MS: m/z 432.1 (M+H+ )。 (S )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉係使用相同程序製備。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.35 (s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.27-4.21 (m, 1H), 4.17-4.12 (m, 1H), 4.08-4.05 (m, 1H), 3.84-3.77 (m, 1H), 3.11-3.03 (m, 1H), 2.76 (t,J = 8.0 Hz, 4H), 2.65 (t,J = 7.6 Hz, 4H), 2.33-2.27 (m, 3H), 1.97-1.83 (m, 4H)。MS: m/z 432.1 (M+H+ )。實例 42 下文顯示(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺之合成。 步驟 1 在N2 下將1-乙醯基-1,2-二氫-吡唑-3-酮(10.0 g, 0.79 mmol)、(S )-環氧乙-2-基甲醇(7.0 g, 95 mmol)及PPh3 (31.0 g, 118.5 mmol)於THF (100 mL)中之混合物冷卻至0℃。向混合物中緩慢添加THF (25 mL)中之DIAD (23.3 mL, 118.5 mmol)。將反應於0℃下再攪拌1小時。在室溫下將反應攪拌過夜。將反應混合物在真空中濃縮並藉由矽膠管柱(PE/EA = 10/1)純化殘餘物，從而產生白色固體狀(S )-1-乙醯基-2-(環氧乙-2-基甲基)-1H -吡唑-3(2H )-酮(10.1 g，產率：70%)。1 H NMR (400 MHz, CDCl3 ): δ = 8.07 (d,J = 2.8 Hz, 1H), 6.00 (d,J = 2.8 Hz, 1H), 4.56-4.51 (m, 1H), 4.21-4.15 (m, 1H), 3.41-3.34 (m, 1H), 2.93-2.89 (m, 1H), 2.77-2.74 (m, 1H), 2.58 (s, 3H)。步驟 2 於0℃下向(S )-1-乙醯基-2-(環氧乙-2-基甲基)-1H -吡唑-3(2H )-酮(55.0 g, 300 mmol)於AcOH (52 mL, 900 mmol)及THF (250 mL)中之溶液中分批添加LiCl.H2 O (29.0 g, 480 mmol)。隨後在室溫下將反應物攪拌過夜。在真空中移除AcOH及THF後，將殘餘物分配在EA (200 mL)與水(200 mL)之間。用EA (50 mL × 4)萃取水層。將合併之有機層用飽和NaHCO3 溶液及鹽水(100 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮，從而產生無色油狀粗製(S )-1-乙醯基-2-(3-氯-2-羥丙基)-1H -吡唑-3(2H )-酮(59.0 g, 90%)，其未經任何純化即用於下一步驟。1 H NMR (400 MHz, CDCl3 ): δ = 8.07 (d,J = 3.2 Hz, 1H), 6.00 (d,J = 3.2 Hz, 1H), 4.41 (d,J = 4.8 Hz, 2H), 4.28-4.20 (m, 1H), 3.78-3.64 (m, 2H), 2.58 (s, 3H)。步驟 3 將(S )-1-乙醯基-2-(3-氯-2-羥丙基)-1H -吡唑-3(2H )-酮(65.4 g, 0.3 mol)、K2 CO3 (82.8 g, 0.6 mol)及KI (9.96 g, 60 mmol)於DMF (500 mL)中之混合物於130℃下攪拌過夜。在減壓下移除溶劑。藉由矽膠管柱(EA)純化殘餘物，從而產生白色固體狀(S )-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-醇(27.6 g，產率：66%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.22 (d,J = 2.0 Hz, 1H), 5.44 (d,J = 2.0 Hz, 1H), 4.28-4.09 (m, 4H), 3.94-3.87 (m, 1H)。步驟 4 向(S )-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-醇(28.0 g, 0.2 mol)於吡啶(200 mL)中之溶液中添加甲磺醯氯(23.0 g, 0.2 mol)。將反應於室溫下攪拌30 min。將反應溶液在真空中濃縮至乾燥並將殘餘物分配在EA (300 mL)與水(500 mL)之間。用EA (300 mL)萃取水層。將合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥，過濾並在真空中濃縮至乾燥，從而產生白色固體狀(S )-甲烷磺酸6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基酯(44.0 g，產率：99%)，其未經任何純化即用於下一步驟。步驟 5 將(S )-甲烷磺酸6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基酯(44.0 g, 0.2 mol)及NaN3 (26.0 g, 0.4 mol)於無水DMF (300 mL)中之混合物於120℃下攪拌2 hr。隨後混合物未經任何純化即直接用於下一步驟。步驟 6 將(R )-6-疊氮基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(DMF中之粗製溶液)、Boc2 O (44 g, 0.2 moL)及Pd/C (3.0 g)於MeOH (300 mL)中之溶液於室溫下在氫氣氛(50 Psi)下攪拌16 hr。反應混合物過濾並在真空中濃縮至乾燥。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生白色固體狀(R )-(6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(30 g, 63%)。步驟 7 於0℃下向(R )- (6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(14.0 g, 60.0 mmol)於MeCN (200 mL)中之溶液中逐份添加NBS (10.7 g, 60.0 mmol)並將反應於室溫下攪拌2 hr。過濾後，濃縮濾液。藉由矽膠管柱(PE/EA = 1/2)純化殘餘物，從而產生黃色固體狀(R )-(3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(20.5 g, 粗製)。MS: m/z 320.0 (M+H+ )。步驟 8 向(R )-(3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(20.5 g, 64.4 mmol)於DMF (150 mL)中之溶液中添加NaH (60%於礦物油中, 5.2 g, 130.0 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加碘甲烷(46.0 g, 320.0 mmol)並將混合物於室溫下攪拌2 hr。將反應混合物倒入水(300 mL)中並用EA (300 mL)萃取。將有機層用水(150 mL)、鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 3/1)純化殘餘物，從而產生白色固體狀(R )-(3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(18 g，產率：90%)。MS: m/z 334.0 (M+H+ )。步驟 9 (R )-6-((第三丁氧基羰基)(甲基)胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經純化即用於下一步驟。步驟 10 將(R )-6-((第三丁氧基羰基)(甲基)胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯(粗製)及NH3 .H2 O (12.0 mL)於THF (50.0 mL)中之溶液於60℃下攪拌16 hr。將混合物在真空中濃縮。藉由矽膠管柱(DCM/MeOH = 25/1)純化殘餘物，從而產生黃色固體狀(R )-甲基(3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(1.8 g，產率：25%，2個步驟)。MS: m/z 333.1 (M+H+ )。步驟 11 (R )-(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯係如製法 D 中合成，從而產生黃色固體狀期望產物(230 mg，產率：96%)。步驟 12 向(R )-(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(230 mg, 0.43 mmol)於CH2 Cl2 (2 mL)中之溶液中添加TFA (0.6 mL)並將混合物於室溫下攪拌30 min。隨後將混合物在真空中濃縮以移除溶劑。將殘餘物用2 M NaOH溶液處理至pH ＞ 13。藉由反相HPLC (0%-50% H2 O中之MeCN)純化所得溶液，從而產生白色固體狀(s)-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(150.0 mg, 80%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.41 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 4.26 (d,J = 9.2 Hz, 1H), 4.19-4.07 (m, 2H), 3.84-3.80 (m, 1H), 3.09 (br, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 2.34 (s, 3H), 1.94-1.87 (m, 4H)。MS: m/z 432.1 (M+H+ )。實例 43 下文顯示外消旋 - 6-(乙基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1~3 該三個步驟類似於((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之一般程序。步驟 4 外消旋 - 乙基(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯係如製法 F 中所述合成以遞送白色固體狀期望產物(100 mg，產率：64%)。MS: m/z 546.3 (M+H+ )步驟 5 向外消旋 - 乙基(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(100 mg, 0.2 mmol)於CH2 Cl2 (2 mL)中之溶液中添加TFA (1 mL)並將混合物於室溫下攪拌30 min。隨後濃縮混合物以移除溶劑。將殘餘物與CH2 Cl2 (5 mL x3)共蒸發且隨後藉由反相HPLC [0%-95% H2 O中之MeCN (0.1% NH3 .H2 O)]純化，從而產生白色固體狀外消旋 - 6-(乙基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(60 mg, 73%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.91 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.41 (dd,J = 11.2, 2.4 Hz, 1H), 4.31 (dd,J = 10.8, 4.8 Hz, 1H), 4.24 (dd,J = 12.8, 4.4 Hz, 1H), 3.95 (dd,J = 12.8, 4.4 Hz, 1H), 3.33 (重疊, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.68-2.58 (m, 6H), 2.00-1.91 (m, 4H), 1.01 (t,J = 7.2 Hz, 3H)。MS: m/z 446.1 (M+H+ )。實例 44 下文顯示(R )-6-(乙基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺鹽酸鹽及(S )-6-(乙基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺鹽酸鹽之合成。 步驟 1 藉由手性prep-HPLC拆分外消旋 - 乙基(3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(120 mg)，從而產生(R )-乙基(3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(峰1, 52 mg)及(S )-乙基(3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(峰2, 48 mg)。步驟 2 此步驟類似於外消旋 - 6-(乙基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之一般程序。步驟 3 向(R )-乙基(3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(40 mg, 0.1 mmol)於CH2 Cl2 (2 mL)中之溶液中添加TFA (1 mL)並將混合物於室溫下攪拌30 min。隨後濃縮混合物以移除溶劑。將殘餘物與CH2 Cl2 (5 mL x3)共蒸發且隨後用飽和NaHCO3 中和至pH = 8。將所得溶液用aq.HCl (2 N)酸化至pH = 5且隨後藉由反相HPLC [0%-95% H2 O中之MeCN]純化，從而產生白色固體狀(R )-6-(乙基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺鹽酸鹽(15 mg, 22%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.74 (s, 1H), 7.52 (s, 1H), 6.88 (s, 1H), 4.38-4.33 (m, 1H), 4.24-4.17 (m, 2H), 3.92-3.85 (m, 1H), 3.32 (重疊, 1H), 2.77 (t,J = 7.2 Hz, 4H), 2.64-2.59 (m, 6H), 2.00-1.89 (m, 4H), 1.00 (t,J = 7.2 Hz, 3H)。MS: m/z 446.1 (M+H+ )。 (S )-6-(乙基胺基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺鹽酸鹽係使用相同程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.89 (s, 1H), 7.60 (s, 1H), 6.93 (s, 1H), 4.41 (dd,J = 10.8, 2.4 Hz, 1H), 4.31 (dd,J = 10.8, 5.2 Hz, 1H), 4.24 (dd,J = 12.4, 4.4 Hz, 1H), 3.95 (dd,J = 12.4, 4.4 Hz, 1H), 3.00 (重疊, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.63-2.58 (m, 6H), 1.97-1.93 (m, 4H), 1.01 (t,J = 7.2 Hz, 3H)。MS: m/z 446.1 (M+H+ )。實例 45 下文顯示(R )-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 於-10℃下在N2 下向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(3.0 g, 17.3 mmol)於THF/H2 O/HBF4 (45 mL/7mL/22mL)中之溶液中逐滴添加NaNO2 (1.3 g, 18.2 mmol)於H2 O (3 mL)中之溶液。在冷卻下攪拌2 hr後，移除冷浴並將反應物分配在水(100 mL)與EA (100 mL)之間。將有機層用NaHCO3 (50 mL)、鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE)純化殘餘物，從而產生白色固體狀4-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(1.4 g，產率：46%)。1 H NMR (300 MHz, CDCl3 ): δ = 6.88 (s, 1H), 2.92-2.87 (m, 8H), 2.17-2.07 (m, 4H)。步驟 2 於0℃下在N2 下向4-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(1.4 g, 8.0 mmol)於MeCN (20 mL)中之溶液中，取NO2 BF4 (1.3 g, 9.8 mmol)分成兩份添加。隨後將反應於0℃下攪拌1 hr。將反應物分配在EA (100 mL)與水(100 mL)之間。將有機層用水(20 mL)及鹽水(20 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由二氧化矽驟沸塔(0% ~ 45% PE中之EA)純化殘餘物，從而產生白色固體狀4-氟-8-硝基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(1.4 g，產率：80%)。1 H NMR (400 MHz, CDCl3 ): δ = 3.30 (t,J = 6.8 Hz, 4H), 2.95 (t,J = 7.6 Hz, 4H), 2.22-2.13 (m, 4H)。步驟 3 向4-氟-8-硝基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯(1.4 g, 6.3 mmol)於MeOH (20 mL)中之溶液中添加10% Pd/C (200 mg)。於室溫下在氣球氫氣氛下攪拌過夜後，過濾反應混合物。將濾液在真空中蒸發至乾燥並藉由二氧化矽驟沸塔(0% ~ 45% PE中之EA)純化殘餘物，從而產生白色固體狀8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(1.1 g，產率：91%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 4.42 (s, 2H), 2.75 (t,J = 7.6 Hz, 4H), 2.62 (t,J = 7.6 Hz, 4H), 2.05-1.97 (m, 4H)。MS: m/z 192.4 (M+H+ )。步驟 4 (R )-(3-(N-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯係如製法 D 中合成，從而產生黃色固體狀期望產物(1.8 g，產率：72%)。MS: m/z 550.2 (M+H+ )。步驟 5 向(R )-(3-(N-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(1.8 g, 3.3 mmol)於CH2 Cl2 (8 mL)中之溶液中添加TFA (8 mL)並將混合物於室溫下攪拌30 min。隨後將混合物在真空中濃縮以移除溶劑。將殘餘物用2 N aq.NaOH處理至PH ＞ 13。藉由反相HPLC (MeCN/H2 O)純化所得溶液，從而產生黃色固體狀(R )-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(1.2 g, 80%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.32 (s, 1H), 4.28-4.24 (m, 1H), 4.16 (q,J = 4.8 Hz, 1H), 4.09 (q,J = 6.0 Hz, 1H), 3.82 (q,J = 5.2 Hz, 1H), 3.08 (br, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.71 (t,J = 7.6 Hz, 4H), 2.33 (s, 3H), 1.99-1.93 (m, 4H)。MS: m/z 450.1 (M+H+ )。實例 46 下文顯示(R )-N-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。向(R )-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(80 mg, 0.34 mmol)於THF (10 mL)中之溶液中添加MeONa (54 mg, 1.0 mmol)並將混合物於室溫下攪拌30 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(66 mg, 0.34 mmol)及TEA (102 mg, 1 mmol)於THF (10 mL)中之溶液中一次性添加三光氣(40 mg, 0.14 mmol)並將混合物於室溫下在N2 下攪拌30 min。隨後過濾反應混合物。向上述鈉鹽懸浮液中添加濾液並於室溫下攪拌過夜。其後，將反應溶液分配在EA (10 mL)與水(5 mL)之間。將水相用1 N HCl酸化至pH = 5。藉由過濾收集所形成固體並乾燥，從而產生白色固體狀(R )-N-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(27 mg，產率：17.6 %)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.55 (brs, 1H), 7.91 (brs, 1H), 7.61 (s, 1H), 4.62 (d,J = 11.6 Hz, 1H), 4.35 (d,J = 11.6 Hz, 1H), 4.18-4.27 (m, 2H), 4.06 (s, 1H), 3.35 (s, 3H), 2.82 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.6 Hz, 4H), 1.98-2.05 (m, 4H) MS: m/z 450.8 (M+H+ )。實例 47 下文顯示(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(丙-2-炔-1-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 向外消旋 - N,N-二苄基-6-(3-羥基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(840 mg, 2.1 mmol)於DMF (10 mL)中之溶液中添加NaH (60%於礦物油中, 126.0 mg, 3.2 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加3-溴丙-1-炔(273.0 mg, 2.3 mmol)並將混合物於室溫下攪拌2 hr。將反應混合物倒入水(20 mL)中並用EA (20 mL)萃取。將有機層用水(10 mL)及鹽水(10 mL)洗滌，經Na2 SO4 乾燥並濃縮至乾燥，從而產生黃色固體狀外消旋 - N,N-二苄基-6-(丙-2-炔-1-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(580 mg，產率：63%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.63 (s, 1H), 7.25-7.16 (m, 10H), 4.52-4.17 (m, 11H), 2.55 (s, 1H)。MS: m/z 438.1 (M+H+ )。步驟 2 向外消旋 - N,N-二苄基-6-(丙-2-炔-1-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(115 mg, 0.3 mmol)於CH2 Cl2 (3.0 mL)中之攪拌溶液中添加濃H2 SO4 (16滴，0.32 mL)並於0℃下攪拌10 min。濃縮反應溶液。將殘餘物用飽和NaHCO3 溶液中和。隨後自混合物過濾出固體並藉由反相HPLC (MeCN/H2 O)純化濾液，從而產生黃色固體狀外消旋 - 6-(丙-2-炔-1-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(23.0 mg，產率：34%)。 MS: m/z 258.0 (M+H+ )。步驟 3 外消旋 - ((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(丙-2-炔-1-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺係如製法 D 中合成，從而產生白色固體狀期望產物(20.0 mg，產率：49%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (brs, 1H), 7.85 (s, 1H), 6.92 (s, 1H), 4.63-4.59 (m, 1H), 4.40-4.25 (m, 6H), 3.52 (t,J = 2.4 Hz, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.62 (t,J = 7.2 Hz, 4H), 1.99-1.92 (m, 4H)。MS: m/z 457.1 (M+H+ )。實例 48 下文顯示外消旋 - ((6-(((第三丁氧基羰基)(甲基)胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉之合成。 步驟 1 於0℃下向外消旋 - ((3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)胺基甲酸第三丁基酯(0.3 g, 0.9 mmol)於THF (3 mL)中之溶液中添加NaH (60%, 108 mg, 2.7 mmol)，之後添加MeI (639 mg, 4.5 mmol)。於室溫下攪拌16 hr後，利用添加EA (20 mL)及水(10 mL)淬滅懸浮液。分離有機層。用EA (10 mL)萃取水層。合併有機層，用鹽水(10 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。藉由矽膠管柱(PE/EA = 2/1)純化殘餘物，從而產生黃色油狀外消旋 - ((3-溴-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)(甲基)胺基甲酸第三丁基酯(290 mg，產率：93%)。步驟 2 外消旋 - 6-(((第三丁氧基羰基)(甲基)胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯苯基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經純化即用於下一步驟。步驟 3 外消旋 - 甲基((3-胺磺醯基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-6-基)甲基)胺基甲酸第三丁基酯係如製法 C 中合成，從而產生淺黃色固體狀期望產物(60 mg，產率：經2個步驟16%)。MS: m/z 369.4 (M+Na+ )。步驟 4 ((6-(((第三丁氧基羰基)(甲基)胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉係如製法 D 中合成，從而產生白色固體狀期望產物(28 mg，產率：31%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.33 (s, 1H), 7.31 (s, 1H), 6.75 (s, 1H), 4.28 (d,J = 10.4 Hz, 1H), 4.10-4.0 (m, 2H), 3.80-3.73 (m, 1H), 3.25-3.15 (m, 2H), 2.80 (s, 3H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.50 (重疊, 1H), 1.95-1.85 (m, 4H), 1.41-1.31 (m, 9H)。MS: m/z 546.2 (M+H+ )。實例 49 下文顯示((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-((甲基胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。向外消旋 - ((6-(((第三丁氧基羰基)(甲基)胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉(15 mg, 0.03 mmol)於CH2 Cl2 (2 mL)中之溶液中添加TFA (0.6 mL)並將混合物於室溫下攪拌30 min。隨後將混合物在真空中濃縮以移除溶劑。將殘餘物添加至2 N NaOH溶液中至pH ＞ 13。藉由反相HPLC (MeCN/H2 O)純化所得溶液，從而產生白色固體狀外消旋 - ((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-((甲基胺基)甲基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(10 mg, 80%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.36 (s, 1H), 6.77 (s, 1H), 4.39 (dd,J = 11.2 Hz, 2.8 Hz, 1H), 4.20-4.1(m, 2H), 3.83 (dd,J = 12.4 Hz, 7.6 Hz, 1H), 3.42 (m, 5H), 3.16-3.11 (m, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 1.96-1.86 (m, 4H)。MS: m/z 446.1 (M+H+ )。實例 50 下文顯示(R )-6-乙基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺及(S )-6-乙基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於0℃下在N2 氣氛下向2-乙基丙二酸二甲基酯(1.8 g, 9.6 mmol)於THF (10 mL)中之溶液中逐滴添加LiBH4 (2 M於THF中, 9.6 mL, 19.2 mmol)。將反應混合物在室溫下攪拌16 hr且隨後傾倒至水(40 mL)。將所得溶液濃縮至約5 mL並與EA (50 mL)混合。將混合物劇烈攪拌5 min，用MgSO4 乾燥並濃縮，從而產生無色油狀2-乙基丙烷-1,3-二醇(970 mg，產率：97%)。步驟 2 於0℃下向2-乙基丙烷-1,3-二醇(970 mg, 9.3 mol)及Et3 N (2.4 g, 23.8 mmol)於無水THF (20 mL)中之溶液中添加MsCl (2.2 g, 19.3 mmol)。於室溫下攪拌30 min後，過濾反應混合物。將濾液濃縮至乾燥，從而產生黃色油狀粗製二甲烷磺酸2-乙基丙烷-1,3-二基酯。步驟 3 將二甲烷磺酸2-乙基丙烷-1,3-二基酯(粗製)、1H-吡唑-3(2H)-酮(750 mg, 8.9 mmol)及K2 CO3 (4.3 g, 31.2 mmol)於DMF (40 mL)中之混合物於100℃下加熱16 hr。將反應混合物分配在EA/H2 O (80 mL /200 mL)之間並分離各層。將水層用EA (80 mL x3)萃取並將合併之有機層用鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 3/1)純化殘餘物，從而產生無色油狀外消旋 - 6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(650 mg，產率：48%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.32 (d,J = 1.5 Hz, 1H), 5.48 (d,J = 1.5 Hz, 1H), 4.34-4.26 (m, 2H), 3.95-3.87 (m, 1H), 3.81-3.73 (m, 1H), 2.30-2.19 (m, 1H), 1.60-1.40 (m, 2H), 1.05 (t,J = 7.5 Hz, 3H)。步驟 4 於0℃下將外消旋 - 6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪(650 mg, 4.3 mmol)逐滴添加至ClSO3 H (4 mL)。於80℃下攪拌2 hr後，將反應混合物逐滴添加至冰水/EA (30 mL /20 mL)之混合物中。分離各層並用EA (10 mL x2)萃取水層。將合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色固體狀粗製外消旋 - 6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯。步驟 5 向粗製外消旋 - 6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯氯於THF (3 mL)中之溶液中添加NH3 .H2 O (1 mL)。於60℃下攪拌1 h後，將反應混合物濃縮至乾燥。將殘餘物溶解於MeOH (3 mL)中並用aq.HCl (1 N)酸化至pH = 3。藉由反相HPLC (0% - 95% H2 O中之MeCN)純化殘餘物，從而產生黃色固體狀外消旋 - 6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(200 mg，產率：20%，兩個步驟)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.48 (s, 1H), 7.08 (s, 2H), 4.48-4.44 (m, 1H), 4.21 (dd,J = 12.4, 5.6 Hz, 1H), 4.12-4.07 (m, 1H), 3.81-3.75 (m, 1H), 2.24-2.17 (m, 1H), 1.47-1.32 (m, 2H), 0.96 (t,J = 7.2 Hz, 3H)。步驟 6 藉由手性HPLC分離外消旋 - 6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(200 mg)，從而產生兩種異構物： (R )-6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(峰1, 80 mg)及(S )-6-乙基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(峰2, 83 mg)。步驟 7 (S )-6-乙基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(53 mg，產率：34%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (brs, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.51 (d,J = 2.8 Hz, 1H), 4.48-4.15 (m, 2H), 3.82-3.77 (m, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.20-1.98 (m, 1H), 1.97-1.91 (m, 4H), 1.45-1.11 (m, 2H), 0.96 (t,J = 7.6 Hz, 3H)。MS: m/z 431.1 (M+H+ )。 (R )-6-乙基-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用相同程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.46 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.50 (dd,J = 10.8, 3.2 Hz, 1H), 4.24-4.13 (m, 2H), 3.83-3.78 (m, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.59 (t,J = 7.2 Hz, 4H), 2.21-2.19 (m, 1H), 1.99-1.92 (m, 4H), 1.42-1.35 (m, 2H), 0.95 (t,J = 7.2 Hz, 3H)。MS: m/z 431.1 (M+H+ )。實例 51 下文顯示6-(3-氟氮雜環丁-1-基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯-苯基酯係使用製法 B 合成，從而產生黃色凝膠狀產物，其未經純化即用於下一步驟。步驟 2 將6-(四氫-吡喃-2-基氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸2,4,6-三氯-苯基酯(粗製，約6.6 mmol)、二苄基胺(2.5 g, 12.0 mmol)及THF (20 mL)之混合物於60℃下攪拌過夜。在減壓下濃縮反應直至剩餘10 mL液體。將剩餘溶液用aq.HCl (1 N)酸化至pH = 5並用EA (100 mL x5)萃取。合併有機層，經Na2 SO4 乾燥並濃縮，從而產生黃色固體狀N,N-二苄基-6-((四氫-2H-吡喃-2-基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(1.5 g，產率：51%)。 MS: m/z 484.2 (M+H+ )。步驟 3 向N,N-二苄基-6-((四氫-2H-吡喃-2-基)氧基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(6.1 g, 12.6 mmol)於THF/H2 O/EtOH (50 mL/10 mL/50 mL)中之溶液中添加濃HCl (10 mL)並將混合物於室溫下攪拌過夜。在減壓下濃縮反應。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生白色固體狀N,N-二苄基-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(4.0 g，產率：80%)。MS: m/z 400.1 (M+H+ )。步驟 4 將N,N-二苄基-6-羥基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(3.4 g, 8.5 mmol)及戴斯-馬丁過碘烷(Dess-Martin periodiane) (7.2 g, 17.0 mmol)於CH2 Cl2 (50.0 mL)中之溶液於室溫下攪拌16 hr。將混合物在真空中濃縮。藉由矽膠管柱層析(PE:EA = 1:2)純化殘餘物，從而產生黃色固體狀N,N-二苄基-6-側氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(3.0 g，產率：91%)。步驟 5 於室溫下向N,N-二苄基-6-側氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(397.0 mg, 1.0 mmol)及3-氟氮雜環丁烷鹽酸鹽(224.0 mg, 2.0 mmol)於MeOH (10.0 mL)中之攪拌溶液中添加三乙醯氧基硼氫化鈉(424.0 mg, 2.0 mmol)。於室溫下攪拌30 min後，向混合物中添加氰基三氫硼酸鈉(126 mg, 2.0 mmol)。在室溫下將反應攪拌16 hr並在真空中濃縮。藉由矽膠管柱層析(CH2 Cl2 /MeOH = 5/1)純化殘餘物，從而產生黃色固體狀N,N-二苄基-6-(3-氟氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(160 mg，產率：35%)。步驟 6 向N,N-二苄基-6-(3-氟氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(140 mg, 0.3 mmol)於CH2 Cl2 (3.0 mL)中之溶液中添加濃H2 SO4 (16滴，0.32 mL)並將混合物於室溫下攪拌30 min。濃縮反應溶液。將殘餘物用飽和NaHCO3 溶液中和並過濾。藉由反相HPLC (0%-95% H2 O中之MeCN)純化濾液，從而產生黃色固體狀6-(3-氟氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(60.0 mg，產率：71%)。步驟 7 6-(3-氟氮雜環丁-1-基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 F 中所述合成以遞送期白色固體狀望產物(11.0 mg，產率：11%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (brs, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 6.93 (s, 1H), 5.20-5.17 (m, 0.5H), 5.06-5.03 (m, 0.5H), 4.32 (q,J = 6.0 Hz, 2H), 4.17 (dd, J = 12.8, 4.0 Hz, 1H), 3.89 (d,J = 13.2 Hz, 1H), 3.65-3.60 (m, 2H), 3.28 (重疊, 2H), 3.09 (d,J = 4.0 Hz, 1H), 2.79 (t,J = 7.6 Hz, 4H), 2.61 (t,J = 7.6 Hz, 4H), 1.99-1.94 (m, 4H)。MS: m/z 476.1 (M+H+ )。實例 52 下文顯示((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(吡咯啶-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 向6-側氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸二苄基醯胺(750 mg, 1.9 mmol)及吡咯啶(270 mg, 3.8 mmol)於MeOH (18 mL)中之溶液中添加AcOH直至pH = 6。隨後添加NaBH(OAc)3 (810 mg, 3.8 mmol)並將反應混合物於室溫下攪拌3 hr。添加NaBH3 CN (240 mg, 3.8 mmol)並將反應混合物於室溫下再攪拌16 hr。將反應溶液濃縮至約6 mL且隨後藉由反相HPLC (0%-95% H2 O中之MeCN)純化，從而產生樹膠狀黃色固體狀6-吡咯啶-1-基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸二苄基醯胺(290 mg，產率：34%)。MS: m/z 453.1 (M+H+ )步驟 2 此步驟類似於6-(3-氟氮雜環丁-1-基)-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之一般程序。步驟 3 向6-吡咯啶-1-基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺酸醯胺(50 mg, 0.2 mmol)於THF (2 mL)中之懸浮液中添加MeONa (35 mg, 0.6 mmol)並將混合物於室溫下攪拌20 min，從而產生鈉鹽懸浮液。 在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(30 mg, 0.2 mmol)及TEA (50 mg, 0.5 mmol)於THF (3 mL)中之溶液中一次性添加光氣(20 mg, 0.1 mmol)並將混合物於室溫下在N2 下攪拌20 min。隨後過濾反應混合物。向上述鈉鹽懸浮液中添加濾液。於室溫下攪拌16 hr，將反應溶液分配在EA (10 mL)與水(30 mL)之間。將水相藉由N2 鼓泡5 min且隨後藉由反相HPLC (0%-95% H2 O中之MeCN)純化，從而產生白色固體狀((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(吡咯啶-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉(10 mg，產率：12%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (s, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 4.50-4.40 (m, 2H), 4.27 (dd,J = 12.8, 4.0 Hz, 1H), 4.13 (dd,J = 12.8, 4.0 Hz, 1H), 2.94-2.91 (m, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.68-2.58 (m, 8H), 2.00-1.91 (m, 4H), 1.70-1.60 (m, 4H)。MS: m/z 472.1 (M+H+ )。實例 53 ((6-(氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉標題化合物係使用((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(吡咯啶-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之一般程序製備。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.33 (s, 1H), 6.77 (s, 1H), 4.15-4.02 (m, 3H), 3.75 (dd,J = 12.8, 1.6 Hz, 1H), 3.20 (t,J = 6.8 Hz, 4H), 2.84-2.80 (m, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 1.97-1.87 (m, 6H)。MS: m/z 458.1 (M+H+ )。實例 54 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於-78℃下在N2 下向TiCl4 (0.5 mL，過量)及甲基溴化鎂(1.0 mL，過量)於THF (5.0 mL)中之攪拌溶液中添加N,N-二苄基-6-側氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(140.0 mg, 0.4 mmol)。隨後過濾混合物並藉由矽膠管柱層析(CH2 Cl2 /MeOH = 25/1)純化濾液，從而產生白色固體狀N,N-二苄基-6-羥基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(55 mg，產率：38%)。步驟 2 向N,N-二苄基-6-羥基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(55 mg, 0.1 mmol)於CH2 Cl2 (3.0 mL)中之攪拌溶液中添加濃H2 SO4 (8滴，0.16 mL)並於室溫下攪拌30 min。濃縮反應溶液。將殘餘物用飽和NaHCO3 溶液中和。隨後過濾混合物並藉由反相HPLC (MeCN/H2 O)純化濾液，從而產生白色固體狀6-羥基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(26.0 mg，產率：87%)。步驟 3 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-羥基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 F 中所述合成以遞送白色固體狀期望產物(7.0 mg，產率：15%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.4 (s, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.45 (s, 1H), 4.18 (s, 2H), 4.04 (d,J = 12.4 Hz, 1H), 3.91 (d,J = 12.0 Hz, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.61 (t,J = 7.2 Hz, 4H), 1.99-1.92 (m, 4H), 1.25 (s, 3H)。MS: m/z 433.1 (M+H+ )。實例 55 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 向N,N-二苄基-6-羥基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(35 mg, 0.08 mmol)於DMF (3 mL)中之溶液中添加NaH (60%於礦物油中, 6.4 mg, 0.16 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加碘甲烷(60 mg, 0.4 mmol)並將混合物於室溫下攪拌2 hr。將反應混合物倒入水(20 mL)中並用EA (20 mL)萃取。將有機層用水(10 mL)及鹽水(10 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由反相HPLC (MeCN/H2 O)純化殘餘物，從而產生黃色油狀N,N-二苄基-6-甲氧基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(30 mg，產率：83%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.58 (s, 1H), 7.29-7.26 (m, 5H), 7.18-7.15 (m, 5H), 4.34 (s, 4H), 4.21 (s, 3H), 4.16 (s, 2H), 2.67 (s, 2H), 1.38 (s, 3H)。 MS: m/z 428.0 (M+H+ )。步驟 2 向N,N-二苄基-6-甲氧基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(25 mg, 0.06 mmol)於CH2 Cl2 (3.0 mL)中之攪拌溶液中添加濃H2 SO4 (8滴，0.16 mL)並將混合物於室溫下攪拌30 min。濃縮反應溶液。將殘餘物用飽和NaHCO3 溶液中和。隨後過濾混合物並藉由反相HPLC (MeCN/H2 O)純化濾液，從而產生黃色固體狀6-甲氧基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(6.0 mg，產率：35%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.57 (s, 1H), 4.09 (s, 3H), 3.89 (q,J = 10.4 Hz, 2H), 3.66 (q,J = 10.0 Hz, 2H), 1.24 (s, 3H)。 MS: m/z 247.9 (M+H+ )。步驟 3 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6-甲氧基-6-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 D 中合成，從而產生白色固體狀期望產物(7.0 mg，產率：73%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 6.80 (s, 1H), 4.15 (s, 3H), 4.01 (s, 2H), 2.75 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 8.4 Hz, 4H), 2.58 (重疊, 2H), 1.92-1.88 (m, 4H), 1.20 (s, 3H)。MS: m/z 447.1 (M+H+ )。實例 56 下文顯示外消旋 - ((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 於室溫下向N,N-二苄基-6-側氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(794 mg, 2.0 mmol)及氮雜環丁-3-醇鹽酸鹽(440.0 mg, 4.0 mmol)於MeOH (30.0 mL)中之攪拌溶液中添加三乙醯氧基硼氫化鈉(848.0 mg, 4.0 mmol)。隨後將混合物於室溫下攪拌30 min。向混合物中添加氰基三氫硼酸鈉(252.0 mg, 4.0 mmol)並於室溫下攪拌16 hr。將混合物在真空中濃縮。藉由矽膠管柱層析(CH2 Cl2 /MeOH=5/1)純化殘餘物，從而產生黃色固體狀外消旋 - N,N-二苄基-6-(3-羥基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(340 mg，產率：37%)。MS: m/z 455.2 (M+H+ )。步驟 2 向外消旋 - N,N-二苄基-6-(3-羥基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(105 mg, 0.2 mmol)於DMF (3 mL)中之溶液中添加NaH (60%於礦物油中, 14.0 mg, 0.4 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加碘甲烷(39.0 mg, 0.3 mmol)並將混合物於室溫下攪拌2 hr。將反應混合物倒入水(20 mL)中並用EA (20 mL)萃取。將有機層用水(10 mL)及鹽水(10 mL)洗滌，經Na2 SO4 乾燥並濃縮至乾燥，從而產生黃色油狀外消旋 - N,N-二苄基-6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(120 mg, 粗製)。 MS: m/z 469.1 (M+H+ )。步驟 3 向外消旋 - N,N-二苄基-6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(120 mg, 0.3 mmol)於CH2 Cl2 (3.0 mL)中之攪拌溶液中添加濃H2 SO4 (16滴，0.32 mL)並於室溫下攪拌30 min。濃縮反應溶液。將殘餘物用飽和NaHCO3 溶液中和。隨後自混合物過濾出固體並藉由反相HPLC (MeCN/H2 O)純化濾液，從而產生白色固體狀外消旋 - 6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(52.0 mg，產率：70%)。MS: m/z 289.1 (M+H+ )。步驟 4 外消旋 - ((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉係如製法 D 中合成，從而產生白色固體狀期望產物(10.0 mg，產率：11%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.85 (brs, 1H), 7.57 (s, 1H), 6.92 (s, 1H), 4.30-4.28 (m, 2H), 4.17-4.12 (m, 1H), 3.91-3.84 (m, 2H), 3.52 (t,J = 7.2 Hz, 2H), 3.14 (s, 3H), 3.01-2.94 (m, 3H), 2.79 (t,J = 7.2 Hz, 4H), 2.62 (t,J = 7.2 Hz, 4H), 1.99-1.92 (m, 4H)。MS: m/z 488.2 (M+H+ )。實例 57 下文顯示(R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉及(S )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 藉由手性prep-HPLC拆分外消旋 - 6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(150 mg)，從而產生白色固體狀(R )-6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(65 mg)及白色固體狀(S )-6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(60 mg)。步驟 2 (R )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉係如製法 D 中合成，從而產生白色固體狀期望產物(54.0 mg，產率：48%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.37 (brs, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.13-4.08 (m, 3H), 3.96-3.92 (m, 1H), 3.79-3.76 (m, 1H), 3.55-3.53 (m, 2H), 3.14 (s, 3H), 2.98-2.94 (m, 2H), 2.87 (br, 1H), 2.75 (t,J = 6.8 Hz, 4H), 2.66 (t,J = 6.8 Hz, 4H), 1.92-1.89 (m, 4H)。MS: m/z 488.2 (M+H+ )。 (S )-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-(3-甲氧基氮雜環丁-1-基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉係使用相同程序製備。1 H NMR (400 MHz, DMSO-d6 ): δ = 7.39 (brs, 1H), 7.30 (s, 1H), 6.76 (s, 1H), 4.12-4.06 (m, 3H), 3.95-3.92 (m, 1H), 3.79-3.76 (m, 1H), 3.55-3.52 (m, 2H), 3.14 (s, 3H), 2.98-2.92 (m, 2H), 2.88 (br, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 1.95-1.87 (m, 4H)。MS: m/z 488.2 (M+H+ )。實例 58 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺醯胺之合成。 步驟 1 向2-溴乙醇(3.8 g, 30.0 mmol)及DHP (2.5 g, 30.0 mmol)於DCM (50 mL)中之溶液中逐份添加TsOH (380.0 mg, 2.2 mmol)並將混合物於室溫下攪拌2 hr。濃縮反應並藉由矽膠管柱(PE/EA = 50/1)純化，從而產生無色油狀2-(2-溴乙氧基)四氫-2H-吡喃(5.6 g，產率：89 %)。1 H NMR (400 MHz, CDCl3 ): δ = 4.68 (t,J = 3.2 Hz, 1H), 4.05-3.99 (m, 1H), 3.92-3.86 (m, 1H), 3.80-3.74 (m, 1H), 3.54-3.49 (m, 3H), 1.85-1.71 (m, 3H), 1.65-1.53 (m, 3H)。步驟 2 向3-硝基-1H-吡唑-5-甲酸(1.57 g, 10.0 mmol)於MeOH (20 mL)中之溶液中添加濃H2 SO4 (2.0 mL)。將所得混合物於65℃下攪拌過夜。隨後將混合物在真空中濃縮，從而產生殘餘物，藉由矽膠管柱(DCM/MeOH = 50/1)對其進行純化，從而得到黃色固體狀3-硝基-1H-吡唑-5-甲酸甲基酯(1.42 g，產率：83%)。1 H NMR (400 MHz, DMSO-d 6 ):δ = 15.24 (brs, 1H), 7.54 (s, 1H), 3.90 (s, 3H)。步驟 3 向3-硝基-1H-吡唑-5-甲酸甲基酯(1.7 g, 10.0 mmol)於NMP (20 mL)中之溶液中添加2-(2-溴乙氧基)四氫-2H-吡喃(2.6 g, 13.0 mmol)，之後添加K2 CO3 (1.7 g, 13.0 mmol)。將所得混合物於80℃下攪拌16 hr。隨後過濾K2 CO3 。在真空中濃縮濾液，從而產生殘餘物，藉由矽膠管柱(PE/EA = 2/1)對其進行純化，從而得到黃色油狀3-硝基-1-(2-((四氫-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-5-甲酸甲基酯(2.8 g，產率：94%)。1 H NMR (400 MHz, CDCl3 ):δ = 7.39 (s, 1H), 4.92 (t,J = 7.2 Hz, 2H), 4.57 (s, 1H), 4.11-4.07 (m, 1H), 3.98 (重疊, 1H), 3.96 (s, 3H), 3.84-3.80 (m, 1H), 3.64-3.60 (m, 1H), 3.49-3.46 (m, 1H), 1.67-1.46 (m, 6H)。步驟 4 於0℃下向3-硝基-1-(2-((四氫-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-5-甲酸甲基酯(2.5 g, 8.4 mmol)於無水THF (50 mL)中之溶液中添加LiBH4 (6.3 mL, 2.0 M於THF中)。將所得混合物自0℃至室溫攪拌3 hr。隨後藉由添加MeOH (4 mL)淬滅反應。將混合物在真空中濃縮，從而產生殘餘物，藉由矽膠管柱(PE/EA = 1/1)對其進行純化，從而得到黃色油狀(3-硝基-1-(2-((四氫-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-5-基)甲醇(2.2 g，產率：96%)。1 H NMR (300 MHz, CDCl3 ):δ = 6.88 (s, 1H), 4.69 (t,J = 6.3 Hz, 2H), 4.57-4.49 (m, 3H), 4.21-4.16 (m, 1H), 3.92-3.85 (m, 1H), 3.77-3.65 (m, 2H), 3.51-3.42 (m, 2H), 1.72-1.48 (m, 6H)。步驟 5 於0℃下向(3-硝基-1-(2-((四氫-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-5-基)甲醇(2.0 g, 7.5 mmol)、吡啶(593 mg, 7.5 mmol)及過溴甲烷(5.0 g, 15.0 mmol)於無水Et2 O (30 mL)中之攪拌溶液中添加三苯基膦(3.9 g, 15.0 mmol)。將所得混合物自0℃至室溫攪拌3 hr。將反應於室溫下攪拌16 hr。隨後自反應過濾出固體並將溶劑在真空中濃縮至乾燥，從而產生黃色膠，藉由矽膠管柱(PE/EA = 1/1)對其進行純化，從而得到黃色油狀5-(溴甲基)-3-硝基-1-(2-((四氫-2H-吡喃-2-基)氧基)乙基)-1H-吡唑(1.5 g，產率：60%)。1 H NMR (400 MHz, CDCl3 ):δ = 6.89 (s, 1H), 4.69 (t,J = 16.0 Hz, 2H), 4.57-4.48 (m, 3H), 4.16-4.10 (m, 1H), 3.84-3.77 (m, 1H), 3.64-3.57 (m, 1H), 3.48-3.43 (m, 1H), 1.72-1.45 (m, 6H)。步驟 6 ： 向5-(溴甲基)-3-硝基-1-(2-((四氫-2H-吡喃-2-基)氧基)乙基)-1H-吡唑(1.5 g, 4.5 mmol)於THF (5 mL)中之溶液中添加濃HCl (1.0 mL)並將混合物於室溫下攪拌16 hr。在減壓下濃縮反應。將殘餘物用飽和NaHCO3 溶液中和並用EA (60 mL)萃取。將有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮至乾燥，從而產生黃色膠，藉由矽膠管柱(PE/EA = 1/1)對其進行純化，從而產生黃色油狀2-(5-(溴甲基)-3-硝基-1H-吡唑-1-基)乙醇(1.0 g，產率：91%)。步驟 7 向2-(5-(溴甲基)-3-硝基-1H-吡唑-1-基)乙醇(1.4 g, 4.47 mmol)於無水THF中之溶液中添加NaH (60%, 197 mg, 4.92 mmol)。於室溫下在N2 下攪拌4 hr後，將反應物分配在水(50 mL)與EA (50 mL)之間。將有機層用鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 4/1)純化殘餘物，從而產生白色固體狀2-硝基-6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪(300 mg，產率：40%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 6.88 (s, 1H), 4.82 (s, 2H), 4.23 (t,J = 4.8 Hz, 2H), 4.12 (t,J = 4.8 Hz, 2H)。步驟 8 向2-硝基-6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪(300 mg, 1.78 mmol)於MeOH (10 mL)中之溶液中添加Pd/C (10%濕，100 mg)。將反應於室溫下在H2 (1 atm)下攪拌3 hr並過濾。濃縮濾液，從而產生黃色膠狀6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-2-胺(250 mg，產率：定量)。MS: m/z 277.0 (M-56+H+ )。1 H NMR (300 MHz, DMSO-d 6 ): δ = 5.20 (s, 1H), 4.63-4.55 (m, 4H), 3.98-3.94 (m, 2H), 3.79-3.75 (m, 2H)。步驟 9 向6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-2-胺(250 mg, 1.8 mmol)於MeCN/H2 O (12 mL/1 mL)中之溶液中添加濃HCl (2.7 mL)及AcOH (1.1 mL)。隨後將混合物冷卻至0℃並緩慢添加NaNO2 (149 mg, 2.2 mmol)於H2 O (1 mL)中之溶液。於0℃下攪拌30 min後，添加CuCl2 (121 mg, 0.9 mmol)及CuCl (9 mg, 0.09 mmol)。隨後使SO2 鼓泡通過反應溶液達10 min。將反應物分配在水(50 mL)與EA (50 mL)之間。將有機層用鹽水(40 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生粗製6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺醯氯，其直接用於下一步驟。步驟 10 向粗製6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺醯氯(粗製，約1.8 mmol)於THF (15 mL)中之溶液中添加氨(5 mL)。將混合物於60℃下攪拌1 hr。濃縮反應，用2 N HCl酸化至pH = 5並藉由反相HPLC (MeCN/H2 O)純化，從而產生白色固體狀6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺醯胺(100 mg，產率：經2個步驟27%)。1 H NMR (300 MHz, DMSO-d6 ): δ = 7.42 (s, 2H), 6.39 (s, 1H), 4.80 (s, 2H), 4.17-4.14 (m, 2H), 4.08 (t,J = 4.8 Hz, 2H)。步驟 11 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(60 mg，產率：30%)。1 H NMR (400 MHz, DMSO-d6 ): δ = 10.86 (brs, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.59 (s, 1H), 4.81 (s, 2H), 4.19 (t,J = 4.8 Hz, 2H), 4.10 (t,J = 4.8 Hz, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.97-1.94 (m, 4H)。MS: m/z 403.0 (M+H+ )。實例 59 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-3,4-二氫-2H-咪唑并[5,1-b][1,3]噁嗪-8-磺醯胺之合成。 步驟 1 於0℃下向3-溴-1-丙醇(4 g, 28.8 mmol)於DCM (50 mL)中之溶液中添加TsOH (496 mg, 2.88 mmol)及3,4-2H-二氫吡喃(7.2 g, 86.2 mmol)。將混合物在室溫下攪拌過夜。將反應混合物倒入H2 O (100 mL)中。用DCM (70 mL x2)萃取混合物。將合併之萃取物用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮至乾燥。藉由矽膠管柱(PE)純化殘餘物，從而產生紅色固體狀2-(3-溴-丙氧基)-四氫-吡喃(838 mg，產率：57%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 4.60-4.56 (m, 1H), 3.77-3.72 (m, 2H), 3.61-3.56 (m, 2H), 3.47-3.42 (m, 2H), 2.07-2.03 (m, 2H), 1.70-1.61 (m, 2H), 1.51-1.45 (m, 4H)。步驟 2 將5-溴-1H-咪唑(6.6 g, 44.9 mmol)於ClSO3 H (30 mL)中之溶液於180℃下在N2 氣氛下攪拌2 hr。將反應混合物倒入冰水(70 mL)中並過濾。將濾餅用H2 O (30 mL)洗滌並乾燥，從而產生黃色固體狀5-溴-1H-咪唑-4-磺醯氯(7 g，產率：63%)。步驟 3 於室溫下向5-溴-1H-咪唑-4-磺醯氯(4 g, 16.3 mmol)於THF (50 mL)中之溶液中添加TEA (4.5 mL, 32.6 mmol)及二苄基胺(3.2 g, 16.3 mmol)。於室溫下攪拌過夜後，將反應混合物倒入H2 O (100 mL)中並用EA (50 mL x2)萃取。將合併之EA用鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生紅色固體狀5-溴-1H-咪唑-4-磺酸二苄基醯胺(1.4 g，產率：21%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.96 (s, 1H), 7.25-7.19 (m, 6H), 7.12-7.05 (m, 4H), 4.36 (s, 4H)。步驟 4 於室溫下向5-溴-1H-咪唑-4-磺酸二苄基醯胺(1.4 g, 3.2 mmol)於DMF (20 mL)中之溶液中添加K2 CO3 (883 mg, 6.4 mmol)、2-(3-溴-丙氧基)-四氫-吡喃(856 mg, 3.8 mmol)並將混合物於80℃下利用N2 攪拌過夜。向反應混合物中添加矽膠並濃縮至乾燥。藉由矽膠管柱(PE/EA = 3/1至1/1)純化殘餘物，從而產生紅色油狀5-溴-1-[3-(四氫-吡喃-2-基氧基)-丙基]-1H-咪唑-4-磺酸二苄基醯胺(1.6 g，產率：69%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 8.08 (s, 1H), 7.23-7.20 (m, 6H), 7.13-7.10 (m, 4H), 4.55-4.52 (m, 1H), 4.36 (s, 4H), 4.12 (t,J = 6.9 Hz, 2H), 3.72-3.64 (m, 2H), 3.40-3.30 (m, 2H), 2.02-1.95 (m, 2H), 1.80-1.59 (m, 2H), 1.50-1.40 (m, 4H)。步驟 5 於室溫下向5-溴-1-[3-(四氫-吡喃-2-基氧基)-丙基]-1H-咪唑-4-磺酸二苄基醯胺(1.6 g, 3.0 mmol)於THF (10 mL)中之溶液中添加MeOH (5 mL)、aq.HCl (6 mL, 6 N)並將其於室溫下攪拌1 hr。將反應混合物倒入H2 O (50 mL)中並用飽和NaHCO3 中和至pH = 7。用EA (30 mL x2)萃取所得混合物。將合併之EA用鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生紅色油狀5-溴-1-(3-羥基-丙基)-1H-咪唑-4-磺酸二苄基醯胺(1.4 g, 粗製)。步驟 6 向5-溴-1-(3-羥基-丙基)-1H-咪唑-4-磺酸二苄基醯胺(1.4 g, 3.0 mmol)於DMF (20 mL)中之溶液中添加NaH (60%, 145 mg, 3.6 mmol)並將混合物於80℃下在N2 下攪拌4 hr。將反應混合物倒入H2 O (100 mL)中並用EA (50 mL x3)萃取。將合併之EA層用H2 O (60 mL x2)洗滌，經Na2 SO4 乾燥並濃縮至乾燥。藉由prep-HPLC (NH4 HCO3 )純化殘餘物，從而產生無色油狀3,4-二氫-2H-咪唑并[5,1-b][1,3]噁嗪-8-磺酸二苄基醯胺(176 mg，產率：16%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.23-7.18 (m, 6H), 7.15-7.12 (m, 4H), 4.34 (t,J = 5.1 Hz, 2H), 4.26 (s, 4H), 4.08 (t,J = 6.3 Hz, 2H), 2.10-2.06 (m, 2H)。步驟 7 於0℃下向3,4-二氫-2H-咪唑并[5,1-b][1,3]噁嗪-8-磺酸二苄基醯胺(170 mg, 0.44 mmol)於DCM (3 mL)中之溶液中添加濃H2 SO4 (12滴)並將混合物於室溫下攪拌30分鐘。將反應混合物倒入飽和NaHCO3 (20 mL)中且隨後濃縮以移除DCM。將所得溶液中和至pH = 7並過濾。藉由反相HPLC (20% H2 O中之MeCN)純化濾液，從而產生白色固體狀3,4-二氫-2H-咪唑并[5,1-b][1,3]噁嗪-8-磺酸醯胺(60 mg，產率：62%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.32 (s, 1H), 6.87 (s, 2H), 4.33 (t,J = 5.7 Hz, 2H), 4.07 (t,J = 6.3 Hz, 2H), 2.09-2.05 (m, 2H)。步驟 8 N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-3,4-二氫-2H-咪唑并[5,1-b][1,3]噁嗪-8-磺醯胺係如製法 E 中所述合成以遞送白色固體狀期望產物(8 mg，產率：8%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.98 (s, 1H), 7.40 (s, 1H), 6.91 (s, 1H), 4.33 (t,J = 2.4 Hz, 2H), 4.06 (t,J = 2.4 Hz, 2H), 2.80 (t,J = 3.0 Hz, 4H), 2.60 (t,J = 2.4 Hz, 4H), 2.07-2.05 (m, 2H), 1.98-1.92 (m, 4H)。MS: m/z 403.1 (M+H+ )。實例 60 下文顯示N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯 -4-基)胺甲醯基)-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-2-磺醯胺之合成。 步驟 1 向5-硝基-1H -吡唑-3-甲酸甲基酯(100 mg, 0.58 mmol)於DMF (10 mL)中之溶液中添加(2-溴乙基)胺基甲酸第三丁基酯(197 mg, 0.88mmol)及K2 CO3 (240 mg, 1.74 mmol)。隨後將反應混合物於80℃下攪拌3 hr。過濾反應混合物，並在真空中濃縮濾液。藉由矽膠管柱層析(PE/EA = 3/1)純化殘餘物，從而產生黃色固體狀1-(2-((第三丁氧基羰基)胺基)乙基)-3-硝基-1H -吡唑-5-甲酸甲基酯(166 mg, 80%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.57 (s, 1H), 6.96 (t,J = 6.0 Hz, 1H), 4.60 (d,J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.41-3.36 (m, 2H), 1.26 (s, 9H)。步驟 2 向1-(2-((第三丁氧基羰基)胺基)乙基)-3-硝基-1H -吡唑-5-甲酸甲基酯(166 mg, 0.46 mmol)於二噁烷(5 mL)中之溶液中添加HCl (1.15 mL, 4.6 mmol, 4 M於二噁烷中)。隨後將反應混合物於室溫下攪拌6 hr。將反應混合物在真空中濃縮。將殘餘物添加至DMF (10 mL)及K2 CO3 (127 mg, 0.92 mmol)之懸浮液中。將反應混合物於80℃下攪拌過夜並藉由LCMS監測。過濾反應混合物且在真空中濃縮濾液。藉由矽膠管柱層析(DCM/MeOH = 50/1 ~ 10/1)純化殘餘物，從而產生黃色固體狀2-硝基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(65 mg, 68%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.61 (s, 1H), 7.43 (s, 1H), 4.46 (t,J = 6.0 Hz, 2H), 3.72-3.65 (m, 2H)。步驟 3 向2-硝基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(1.2 g, 6.6mmol)於EtOH (30 mL)中之溶液中添加鐵粉(1.8 g, 33.0mmol)、NH4 Cl (1.76 g, 33.0 mmol)及H2 O (10 mL)。將反應混合物於80℃下在N2 中攪拌過夜並藉由LCMS監測。過濾反應混合物且在真空中濃縮濾液。藉由矽膠管柱層析(DCM/MeOH = 10/1)純化粗產物，從而產生黃色固體狀2-胺基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(0.76 g, 76%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.01 (s, 1H), 5.80 (s, 1H), 4.88 (s, 2H), 3.98 (t,J = 5.6 Hz, 2H), 3.54-3.45 (m, 2H)。步驟 4 於0℃下在劇烈攪拌下向CuCl (0.204 g, 2.1 mmol)於H2 O (265 mL)中之懸浮液中逐滴添加SOCl2 (44.85 mL, 0.618 mol)。將溶液於室溫下攪拌過夜，從而產生淺黃色溶液。單獨地，於-10℃下向2-胺基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(0.62 g, 4.1 mmol)於濃HCl (4 mL)中之溶液中逐滴添加NaNO2 (0.33 g. 4.8 mmol)於H2 O (2 mL)中之溶液。將所得深橙色溶液於-10℃下攪拌30分鐘，且隨後於-5℃下經5分鐘添加至來自第一步驟之氯化銅(I)溶液(10.6 mL)中。將反應於-5℃下攪拌1 hr並用EA (10 mL × 3)萃取。在真空中濃縮有機層，從而產生黃色固體。將此固體溶解於THF (20 mL)中，之後於0℃下逐滴添加NH3 (10 mL, 28% wt)。將反應於0℃下攪拌2 hr且隨後在真空中濃縮。藉由矽膠管柱層析(DCM/MeOH = 10/1)純化所得固體，從而產生白色固體狀4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-2-磺醯胺(0.2 g, 23%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.46 (s, 1H), 7.59 (s, 2H), 6.94 (s, 1H), 4.39 (t,J = 5.2 Hz, 2H), 3.70-3.63 (m, 2H)。步驟 5 N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯 -4-基)胺甲醯基)-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-2-磺醯胺係如製法 F 中所述合成以遞送白色固體狀期望產物(8.3 mg, 4.3%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.37 (s, 1H), 7.81 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 6.85 (s, 1H), 4.33 (t,J = 6.0 Hz, 2H), 3.65-3.61 (m, 2H), 2.76 (t,J = 7.2 Hz, 4H), 2.63 (t,J = 6.8 Hz, 4H), 1.96-1.88 (m, 4H)。MS: m/z 414.1 (M - H+ )。實例 61 下文顯示N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基)胺甲醯基)-5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-2-磺醯胺之合成。 步驟 1 於-5℃下向5-硝基-1H -吡唑-3-甲酸(5.0 g, 31.8mmol)及2-(甲基胺基)乙醇(3.58 g, 47.7 mmol)於DCM (50 mL)中之溶液中逐滴添加SOCl2 (11.5 mL, 159 mmmol)及DMF (4滴)達10 min。隨後將反應混合物於50℃下攪拌過夜。在真空中濃縮反應混合物。將殘餘物添加至DMF (50 mL)及TEA (13.3 mL, 95.4 mmol)中。隨後將反應於60℃下攪拌過夜。在真空中移除溶劑後，藉由矽膠管柱層析(DCM/MeOH = 50/1 ~ 10/1)純化殘餘物，從而產生黃色固體狀5-甲基-2-硝基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(4.66 g, 75%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 4.53 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.8 Hz, 2H), 3.03 (s, 3H)。步驟 2 向5-甲基-2-硝基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(700 mg, 3.6mmol)於EtOH (20 mL)中之溶液中添加鐵粉(1.0 g, 17.9mmol)、NH4 Cl (0.96 g, 17.9 mmol)及H2 O (7 mL)。將反應混合物於80℃下在N2 氣氛下攪拌過夜並藉由LCMS監測。過濾反應混合物且在真空中濃縮濾液。藉由矽膠管柱層析(DCM/MeOH = 50/1 ~ 10/1)純化粗產物，從而產生黃色固體狀2-胺基-5-甲基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(0.44 g, 73%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 5.80 (s, 1H), 4.85 (brs, 2H), 4.08 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.4 Hz, 2H), 2.95 (s, 3H)。步驟 3 於-5℃下在劇烈攪拌下向CuCl (0.204 g, 2.1 mmol)於H2 O (265 mL)中之懸浮液中逐滴添加SOCl2 (44.85 mL, 0.618 mol)。將溶液於室溫下攪拌過夜，從而產生淺黃色溶液。單獨地，於-10℃下向2-胺基-5-甲基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(100 mg, 0.6 mmol)於濃HCl (0.97 mL)中之溶液中逐滴添加NaNO2 (50 mg, 0.72 mmol)於H2 O (2 mL)中之溶液。於-5℃下經5分鐘將所得深橙色溶液於-10℃下攪拌30分鐘且隨後添加至上述氯化銅(I)溶液(1.6 mL)中。將反應於-5℃下攪拌1 hr並用EA (10 mL × 3)萃取。在真空中濃縮有機層，從而產生黃色固體。向此固體中添加THF (5 mL)，之後於-5℃下逐滴添加NH3 (3 mL, 28% wt)。將反應於0℃下攪拌2 hr，隨後在真空中濃縮。藉由矽膠管柱層析(DCM/MeOH = 10/1)純化所得固體，從而產生黃色固體狀5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-2-磺醯胺(42 mg, 30%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.60 (s, 2H), 6.93 (s, 1H), 4.46 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.4 Hz, 2H), 3.01 (s, 3H)。步驟 4 N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基)胺甲醯基)-5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-2-磺醯胺係如製法 E 中所述合成以遞送白色固體狀期望產物(21.8 mg, 12%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.70 (s, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 4.39 (t,J = 6.0 Hz, 2H), 3.78 (t,J = 6.4 Hz, 2H), 3.34 (s, 3H), 2.76 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 1.96-1.86 (m, 4H)。MS: m/z 430.0 (M + H+ )。實例 62 下文顯示N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基)胺甲醯基)-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-磺醯胺之合成。 步驟 1 向4-硝基-1H -吡唑-5-甲酸(1.0 g, 6.4 mmol)於MeOH (30 mL)中之溶液中添加TsOH (52 mg, 0.3 mmol)。隨後將反應混合物於65℃下攪拌過夜。在真空中濃縮反應混合物。藉由矽膠管柱層析(DCM/MeOH = 40/1 ~ 10/1)純化殘餘物，從而產生白色固體狀4-硝基-1H -吡唑-5-甲酸甲基酯(1.0 g, 91%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.90 (s, 1H), 3.88 (s, 3H)。步驟 2 向4-硝基-1H -吡唑-5-甲酸酯(3.0 g, 17.5 mmol)於MeOH (100 mL)中之溶液中添加(Boc)2 O (4.2 g, 19.25 mmol)及Pd/C (300 mg, 10% wt)。隨後將反應混合物於40℃下在H2 氣氛下攪拌過夜並藉由LCMS監測。過濾反應混合物且在真空中濃縮濾液。藉由矽膠管柱層析(PE/EA = 2/1 ~ 1/1)純化殘餘物，從而產生白色固體狀4-((第三丁氧基羰基)胺基)-1H -吡唑-5-甲酸甲基酯(2.52 g, 60%)。步驟 3 向4-((第三丁氧基羰基)胺基)-1H -吡唑-5-甲酸甲基酯(4.2g, 17.4mmol)於DMF (50 mL)中之溶液中添加(2-溴乙基)胺基甲酸第三丁基酯(5.8 g, 26.1 mmol)及K2 CO3 (7.2 g, 52.2 mmol)。隨後將反應混合物於80℃下攪拌過夜並藉由LCMS監測。過濾反應混合物且在真空中濃縮濾液。藉由矽膠管柱層析(PE/EA = 3/1)純化殘餘物，從而產生黃色油狀4-((第三丁氧基羰基)胺基)-1-(2-((第三丁氧基羰基)胺基)乙基)-1H -吡唑-5-甲酸甲基酯(1.26 g, 19%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.16 (s, 1H), 7.80 (s, 1H), 6.81 (t,J = 6.8 Hz, 1H), 4.40 (t,J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.29- 3.22 (m, 2H), 1.46 (s, 9H), 1.33 (s, 9H)。步驟 4 向4-((第三丁氧基羰基)胺基)-1-(2-((第三丁氧基羰基)胺基)乙基)-1H -吡唑-5-甲酸甲基酯(1.26 g, 3.3 mmol)於DCM (20 mL)中之溶液中添加CF3 CO2 H (2.4 mL, 33 mmol)。隨後將反應混合物於室溫下攪拌過夜並藉由LCMS監測。在真空中濃縮反應混合物。將殘餘物添加至DMF (20 mL)及K2 CO3 (1.36 mg, 9.9 mmol)之懸浮液中。將反應混合物於80℃下攪拌過夜並藉由LCMS監測。過濾反應混合物且在真空中濃縮濾液。藉由矽膠管柱層析(DCM/MeOH = 20/1 ~ 10/1)純化殘餘物，從而產生白色固體狀3-胺基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(354 mg, 71%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.75 (brs, 1H), 7.00 (s, 1H), 4.68 (brs, 2H), 4.08 (d,J = 5.6 Hz, 2H), 3.55-3.47 (m, 2H)。步驟 5 於0℃下在劇烈攪拌下向CuCl (0.204 g, 2.1 mmol)於H2 O (265 mL)中之懸浮液中逐滴添加SOCl2 (44.85 mL, 0.618 mol)。將溶液於室溫下攪拌過夜，從而產生淺黃色溶液。單獨地，於-10℃下向3-胺基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(155 mg, 1.02 mmol)於濃HCl (1 mL)中之溶液中逐滴添加NaNO2 (84.4 mg. 1.23 mmol)於H2 O (2 mL)中之溶液。將所得深橙色溶液於-10℃下攪拌30分鐘且隨後於-5℃下經5分鐘添加至上述氯化銅(I)溶液(2.65 mL)中。將反應於-5℃下攪拌1 hr且隨後用EA (10 mL × 3)萃取。在真空中濃縮有機層，從而產生黃色固體。將此固體溶解於THF (5 mL)中，之後於0℃下逐滴添加NH3 (4 mL, 28%wt)。將反應於0℃下攪拌2 hr且隨後在真空中濃縮。藉由prep-TLC (DCM/MeOH = 10/1)純化所得固體，從而產生黃色固體狀4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-磺醯胺(5 mg, 2.2%)。步驟 6 N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基)胺甲醯基)-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-磺醯胺係如製法 E 中所述合成以遞送黃色固體狀期望產物(1.1 mg, 5.8%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.64 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 6.87 (s, 1H), 4.38 (d,J = 5.6 Hz, 2H), 3.65-3.59 (m, 2H), 2.77 (t,J = 6.8 Hz, 4H), 2.57 (t,J = 7.2 Hz, 4H), 1.97-1.87 (m, 4H)。MS: m/z 416.1 (M + H+ )。實例 63 下文顯示N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基)胺甲醯基)-5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-磺醯胺之合成。 步驟 1 於-5℃下向4-硝基-1H -吡唑-5-甲酸(1.0 g, 6.4mmol)及2-(甲基胺基)乙醇(0.55 g, 7.3 mmol)於甲苯(5 mL)中之溶液中逐滴添加SOCl2 (20 mL)及DMF (3滴)達10 min。隨後將反應混合物於80℃下攪拌過夜。在真空中濃縮反應混合物。將殘餘物溶解於DMF (20 mL)及TEA (2.7 mL, 19.3 mmol)中。隨後將反應於60℃下攪拌過夜並藉由LCMS監測。在真空中移除溶劑後，藉由矽膠管柱層析(PE/EA = 3/1 ~ 1/1)純化殘餘物，從而產生黃色固體狀5-甲基-3-硝基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(0.7 g, 56%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.34 (s, 1H), 4.47 (t,J = 5.6 Hz, 2H), 3.85 (t,J = 6.4 Hz, 2H), 3.05 (s, 3H)。步驟 2 向5-甲基-3-硝基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(3.52 g, 18mmol)於EtOH (75 mL)中之溶液中添加鐵粉(5.04 g, 90 mmol)、NH4 Cl (4.82 g, 90 mmol)及H2 O (25 mL)。將反應混合物於80℃下在N2 氣氛下攪拌過夜並藉由LCMS監測。過濾反應混合物且在真空中濃縮濾液。藉由矽膠管柱層析(DCM/MeOH = 10/1)純化粗產物，從而產生黃色固體狀3-胺基-5-甲基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(2.58 g, 86%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.01 (s, 1H), 4.76 (s, 2H), 4.16 (t,J = 6.0 Hz, 2H), 3.66 (t,J = 6.4 Hz, 2H), 2.94 (s, 3H)。步驟 3 於-5℃下向水(70 mL)中逐滴添加SOCl2 (20 mL)。將溶液於5℃下攪拌1 hr並於室溫下攪拌1 hr。添加CuCl (0.16 g)，從而產生黃色溶液。將其於室溫下攪拌5 min，隨後冷卻至-10℃。單獨地，於-10℃下向3-胺基-5-甲基-6,7-二氫吡唑并[1,5-a ]吡嗪-4(5H )-酮(358 mg, 2.2 mmol)於濃HCl (2.0 mL)中之溶液中逐滴添加NaNO2 (180 mg, 2.62 mmol)於H2 O (1.6 mL)中之溶液。將所得深橙色溶液於-10℃下攪拌30分鐘且隨後於-5℃下經5分鐘添加至上述氯化銅(I)溶液(5.7 mL)中。將反應於-5℃下攪拌1 hr且隨後用EA (5 mL × 3)萃取。在真空中濃縮有機層，從而產生黃色固體。將此固體溶解於THF (5 mL)中，之後於-5℃下逐滴添加NH3 (3 mL, 28% wt)。將反應於0℃下攪拌2 hr且隨後在真空中濃縮。藉由prep-TLC (DCM/MeOH = 10/1)純化所得固體，從而產生黃色固體狀5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-磺醯胺(30 mg, 6%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (s, 1H), 7.18 (s, 2H), 4.48 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.4 Hz, 2H), 3.06 (s, 3H)。步驟 4 將DMSO (2 mL)中之NaH (6.24 mg，0.156 mmol，石蠟液體中之60%分散液)於70℃下攪拌30 min。隨後於-5℃下向NaH於DMSO (2 mL)中之溶液中添加5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-磺醯胺(30 mg, 0.13mmol)並於-5℃下攪拌30 min。單獨地，於-5℃下向1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-胺(24.8 mg, 0.14 mmol)於THF (5 mL)中之溶液中添加三光氣(15.4 mg, 0.052 mmol)及TEA (0.1 mL)。隨後將反應混合物於-5℃下攪拌30 min並藉由TCL監測。過濾此反應物並於-5℃下將濾液添加至((5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-基)磺醯基)醯胺鈉之上述懸浮液中。將反應於室溫下攪拌過夜並藉由LC-MS監測。隨後將此反應物用飽和NH4 Cl水溶液(5 mL × 3)洗滌。將有機層經無水Na2 SO4 乾燥並在真空中濃縮。藉由prep-HPLC純化殘餘物，從而產生白色固體狀N -((1,2,3,5,6,7-六氫-s- 二環戊二烯并苯-4-基)胺甲醯基)-5-甲基-4-側氧基-4,5,6,7-四氫吡唑并[1,5-a ]吡嗪-3-磺醯胺(12.8 mg, 25%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.27 (brs, 1H), 7.91 (s, 1H), 6.90 (s, 1H), 4.47 (t,J = 5.6 Hz, 2H), 3.83 (t,J = 6.0 Hz, 2H), 3.06 (s, 3H), 2.77 (t,J = 6.8 Hz, 4H), 2.55 (t,J = 7.6 Hz, 4H), 1.99-1.88 (m, 4H)。MS: m/z 430.1 (M+H+ )。實例 64 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]嘧啶-3-磺醯胺之合成。 步驟 1 向1H-吡唑-5-胺(9.8 g, 0.1 mol)及TEA (36.0 g, 0.3 mmol)於1,4-二噁烷(200 mL)中之溶液中添加1,3-二溴丙烷(26.3 g, 0.1 mmol)。於110℃下攪拌5 hr後，過濾反應混合物。將濾液濃縮至乾燥。藉由矽膠管柱(DCM/MeOH = 100/1)純化殘餘物，從而產生白色固體狀4,5,6,7-四氫吡唑并[1,5-a]嘧啶(5.3 g，產率：36%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.18 (s, 1H), 5.26 (s, 1H), 4.22-4.00 (m, 3H), 3.26-3.22 (m, 2H), 2.11-2.03 (m, 2H)。步驟 2 向4,5,6,7-四氫吡唑并[1,5-a]嘧啶(3.0 g, 24.4 mmol)於THF (20 mL)中之溶液中添加NaH (60%於礦物油中, 1.5 g, 36.6 mmol)。將反應於室溫下在N2 下攪拌1 hr。隨後添加Boc2 O (8.0 g, 36.6 mmol)並將混合物於室溫下攪拌16 hr。將反應混合物倒入水(60 mL)中並用EA (50 mL x2)萃取。將有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(DCM/MeOH = 100/1)純化殘餘物，從而產生白色固體狀6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(4.4 g，產率：81%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.37 (s, 1H), 6.28 (s, 1H), 4.21-4.16 (m, 2H), 3.86-3.80 (m, 2H), 2.20-2.15 (m, 2H), 1.57 (s, 9H)。MS: m/z 224.4 (M+H+ )。步驟 3 於0℃下向6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(4.4 g, 19.6 mmol)於MeCN (20 mL)中之溶液中逐份添加NBS (4.2 g, 23.5 mmol)並將反應於室溫下攪拌16 hr。將反應混合物倒入水(40 mL)中並用EA (40 mL x2)萃取。將有機層用水(40 mL)及鹽水(40 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生黃色固體狀3-溴-6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(4.1 g，產率：69%)。MS: m/z 304.3 (M+H+ )。步驟 4 3-((2,4,6-三氯苯氧基)磺醯基)-6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯係使用製法 B 合成，從而產生黃色油狀產物，其未經純化即用於下一步驟。步驟 5 將3-((2,4,6-三氯苯氧基)磺醯基)-6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(粗製，約1.85 mmol)、NH4 OH (5 mL)及THF (20 mL)之混合物於60℃下攪拌12 hr。在減壓下濃縮反應。將剩餘溶液用aq.HCl (1 N)酸化至pH = 5並分配在EA (60 mL)與水(60 mL)之間。將有機層用水(60 mL)、鹽水(60 mL)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生白色固體狀3-胺磺醯基-6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(100 mg，產率：經2個步驟18%)。1 H NMR (300 MHz, CDCl3 ): δ = 7.80 (s, 1H), 5.54 (brs, 2H), 4.23 (t,J = 6.3 Hz,2H), 3.96 (t,J = 6.0 Hz,2H), 2.23-2.19 (m,2H), 1.57 (s, 9H)。MS: m/z 303.1 (M+H+ )。步驟 6 向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(68.7 mg, 0.397 mmol)及TEA (0.16 mL, 1.2 mmol)於THF (5 mL)中之溶液中添加三光氣(47.2 mg, 0.16 mmol)。將混合物於室溫下攪拌20分鐘。在另一圓底燒瓶中，向3-胺磺醯基-6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(120 mg, 0.397 mmol)於THF (5 ml)中之溶液中添加MeONa (23.6 mg, 0.436 mmol)並將混合物於室溫下攪拌20分鐘。過濾所製備之4-異氰酸基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯以移除所得沈澱並將濾液添加至含有磺醯胺鹽之另一燒瓶中。30分鐘後，利用添加水(30 mL)淬滅反應。將水相用EA (20 mL)萃取並過濾。將濾液酸化至pH = 3~4，且將其用EA (20 mLx2)萃取，從而產生白色固體狀3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(32 mg，產率：16%)。步驟 7 向3-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫吡唑并[1,5-a]嘧啶-4(5H)-甲酸第三丁基酯(32 mg, 0.064 mmol)於DCM (2 mL)中之溶液中添加TFA (1 mL)並將混合物溶液於室溫下攪拌30分鐘。藉由LC-MS監測反應，並將反應混合物在真空中濃縮至乾燥。藉由prep-HPLC (NH3·H2O)純化殘餘物，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]嘧啶-3-磺醯胺(11.6 mg，產率：45%)。1 H NMR (300 MHz, DMSO-d 6 ): δ = 8.01 (s, 1H), 7.39 (s, 1H), 6.92 (s, 1H), 6.42 (s, 1H), 3.96 (t,J = 5.6 Hz, 2H), 3.25-3.23 (m, 2H), 2.79 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.97-1.91 (m, 6H)。MS: m/z 402.0 (M+H+ )。實例 65 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]吡嗪-2-磺醯胺三氟乙酸之合成。 步驟 1 向3-硝基-1H-吡唑-5-甲酸(1.57 g, 10.0 mmol)於MeOH (20 mL)中之溶液中添加濃H2 SO4 (2.0 mL)。將所得混合物於65℃下攪拌過夜。隨後將混合物在真空中濃縮，從而產生殘餘物，藉由矽膠管柱(DCM/MeOH = 50/1)對其進行純化，從而得到黃色固體狀3-硝基-1H-吡唑-5-甲酸甲基酯(1.42 g，產率：83%)。1 H NMR (400 MHz, DMSO-d 6 ):δ = 15.24 (brs, 1H), 7.54 (s, 1H), 3.90 (s, 3H)。步驟 2 向3-硝基-1H-吡唑-5-甲酸甲基酯(342 mg, 2.0 mmol)於丙酮(40 mL)中之溶液中添加1,2-二溴乙烷(412 mg, 2.2 mmol)，之後添加K2 CO3 (828 mg, 6.0 mmol)。將所得混合物攪拌回流2 hr。隨後過濾K2 CO3 。在真空中濃縮濾液，從而產生殘餘物，藉由矽膠管柱(DCM/MeOH = 50/1)對其進行純化，從而得到黃色固體狀1-(2-溴乙基)-3-硝基-1H -吡唑-5-甲酸甲基酯(430 mg，產率：77%)。1 H NMR (400 MHz, CDCl3 ):δ = 7.42 (s, 1H), 5.08 (t,J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.78 (t,J = 6.4 Hz, 2H)。步驟 3 於0℃下向1-(2-溴乙基)-3-硝基-1H -吡唑-5-甲酸酯(278 mg, 1.0 mmol)於無水THF (20 mL)中之溶液中添加LiBH4 (2 mL, 2.0 M於THF中)。將所得混合物自0℃至室溫攪拌3 hr。隨後藉由添加MeOH (4 mL)淬滅反應。將混合物在真空中濃縮，從而產生殘餘物，藉由矽膠管柱(DCM/MeOH = 100/1)對其進行純化，從而得到白色固體狀(1-(2-溴乙基)-3-硝基-1H -吡唑-5-基)甲醇(122 mg，產率：49%)。1 H NMR (400 MHz, DMSO-d 6 ):δ = 6.99 (s, 1H), 5.69 (t,J = 5.6 Hz, 1H), 4.66 (t,J = 6.0 Hz, 2H), 4.61 (d,J = 5.6 Hz, 2H), 3.91 (t,J = 6.4 Hz, 2H)。步驟 4 將[2-(2-溴-乙基)-5-硝基-2H-吡唑-3-基]-甲醇(3.0 g, 12.0 mmol)、PBr3 (4.9 g, 18.0 mmol)及CH2 Cl2 (50 mL)之混合物於45℃下攪拌3 hr。將反應物用飽和 NaHCO3 中和並用CH2 Cl2 (60 mL)萃取並將合併之有機層用鹽水(50 mL)洗滌，經Na2 SO4 乾燥，過濾並在真空中濃縮至乾燥，從而產生淺黃色固體狀1-(2-溴-乙基)-5-溴甲基-3-硝基-1H-吡唑(2.2 g，產率：58%)。1 H NMR (300 MHz, CDCl3 ): δ = 6.93 (s, 1H), 4.63 (t,J = 3.8 Hz, 2H), 4.53 (s, 2H), 3.86 (t,J = 4.2 Hz, 2H)。步驟 5 將1-(2-溴-乙基)-5-溴甲基-3-硝基-1H-吡唑(1.5 g, 4.8 mmol)、NH3 . H2 O (8 mL)及MeOH (10 mL)之混合物於50℃下在密封管中攪拌16 hr。將反應混合物在真空中濃縮至乾燥，從而產生白色固體狀2-硝基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪(700 mg，產率：87%)。 MS: m/z 169.0 (M+H+ )。步驟 6 將2-硝基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪(700 mg, 4.2 mmol)、CbzCl (700 mg, 4.2 mmol)、K2 CO3 (1.2 g, 8.4 mmol)及CH3 CN (20 mL)中之混合物於室溫下攪拌16 hr。將反應混合物在真空中濃縮至乾燥。藉由矽膠管柱(PE/EA = 5/1至1/1)純化殘餘物，從而產生黃色固體狀2-硝基-6,7-二氫-4H-吡唑并[1,5-a]吡嗪-5-甲酸苄基酯(900 mg，產率：69%)。步驟 7 將2-硝基-6,7-二氫-4H-吡唑并[1,5-a]吡嗪-5-甲酸苄基酯(710 mg, 2.4 mmol)、Fe (658 mg, 11.8 mmol)、NH4 Cl (637 mg, 11.8 mmol)、H2 O (10 mL)及EtOH (20 mL)之混合物於80℃下攪拌16 hr。經由矽藻土墊過濾反應混合物並用CH2 Cl2 (30 mL)沖洗。將濾液溶液濃縮至乾燥，從而產生黃色油狀2-胺基-6,7-二氫-4H-吡唑并[1,5-a]吡嗪-5-甲酸苄基酯(639 mg，產率：98%)。步驟 8 於0℃下將2-胺基-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸苄基酯(639 mg, 2.4 mmol)於MeCN (8 mL)中之溶液用H2 O (1.2 mL)中之濃HCl (3.0 mL)、之後NaNO2 (198 mg, 2.9 mmol)溶解於H2 O (0.9 mL)中之水溶液處理。將溶液於0℃下攪拌45 min。向上述混合物中依序添加AcOH (1.2 mL)、CuCl2 (162 mg, 1.2 mmol)及CuCl (12 mg, 0.12 mmol)並於0℃下用SO2 氣體吹掃25 min。於0℃下攪拌1 hr後，將反應混合物傾倒至冰水(100 mL)並用EA (40 mL x3)萃取。將合併之有機層經Na2 SO4 乾燥，過濾並在真空中蒸發，從而產生黃色油狀2-(氯磺醯基)-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸苄基酯(粗製)。此物質未經進一步純化即用於下一步驟。步驟 9 向2-(氯磺醯基)-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸苄基酯(粗製)於THF (6 mL)中之溶液中添加NH3 . H2 O (3 mL)。於室溫下攪拌20 min後，將反應混合物濃縮，用MeOH (5 mL)稀釋並由aq.HCl (1 N)酸化至pH = 5。藉由反相HPLC (0%-50% H2 O中之MeCN)純化所得溶液，從而產生白色固體狀2-胺磺醯基-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸苄基酯(122 mg，產率：15%，兩個步驟)。 MS: m/z 337.0 (M+H+ )。步驟 10 將2-胺磺醯基-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸苄基酯(102 mg, 0.3 mmoL)、Boc2 O (73 mg, 0.33 mmoL)及Pd/C (20 mg)於MeOH (10 mL)中之溶液於室溫下在氫氣氛(50 psi)下攪拌16 hr。過濾反應混合物並在真空中濃縮至乾燥。藉由矽膠管柱(CH2 Cl2 /MeOH = 40/1)純化殘餘物，從而產生黃色固體狀2-胺磺醯基-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸第三丁基酯(106 mg，產率：96%)。 MS: m/z 303.0 (M+H+ )。步驟 11 2-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸第三丁基酯係如製法 F 中所述合成以遞送黃色固體狀期望產物(108 mg, 粗製)。 MS: m/z 502.1 (M+H+ )。步驟 12 ： 向2-(N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)胺磺醯基)-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸第三丁基酯(68 mg, 粗製)於CH2 Cl2 (1 mL)中之溶液中添加TFA (0.5 mL)並將混合物於室溫下攪拌30 min。藉由反相HPLC (0%-50% H2 O中之MeCN)純化所得溶液，從而產生白色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]吡嗪-2-磺醯胺TFA鹽(7.9 mg, 15%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.01 (s, 1H), 6.93 (s, 1H), 6.50 (s, 1H), 4.05 (t,J = 4.8 Hz, 2H), 3.93 (s, 2H), 3.17 (t,J = 5.2 Hz, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.61 (t,J = 7.6 Hz, 4H),1.99-1.94 (m, 4H)。MS: m/z 401.9 (M+H+ )。實例 66 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-5-甲基-4,5,6,7-四氫吡唑并[1,5-a]吡嗪-2-磺醯胺之合成。 步驟 1 向2-胺磺醯基-6,7-二氫吡唑并[1,5-a]吡嗪-5(4H)-甲酸第三丁基酯(60 mg, 0.2 mmol)於CH2 Cl2 (1 mL)中之溶液中添加TFA (2 mL)並將混合物於室溫下攪拌30 min。藉由反相HPLC (0% - 50% H2 O中之MeCN)純化所得溶液，從而產生褐色固體狀4,5,6,7-四氫吡唑并[1,5-a]吡嗪-2-磺醯胺TFA鹽(50 mg, 粗製)。MS: m/z 202.9 (M+H+ )。步驟 2 向4,5,6,7-四氫吡唑并[1,5-a]吡嗪-2-磺醯胺TFA鹽(45 mg, 粗製)於MeOH (10 mL)中之攪拌溶液中添加甲醛(40 mg, 1.3 mmol)及氰基硼氫化鈉(14 mg, 0.2 mmol)。於室溫下攪拌2 hr後，將反應混合物濃縮並藉由反相管柱(0% - 50% H2 O中之MeCN)純化，從而產生白色固體狀5-甲基-4,5,6,7-四氫吡唑并[1,5-a]吡嗪-2-磺醯胺(17 mg，產率：32%)。 MS: m/z 217.0 (M+H+ )。步驟 3 ： N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-5-甲基-4,5,6,7-四氫吡唑并[1,5-a]吡嗪-2-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(9.6 mg，產率：29%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.80 (s, 1H), 8.02 (s, 1H), 6.94 (s, 1H), 6.55 (s, 1H), 4.16 (t,J = 5.6 Hz, 2H), 3.62 (s, 2H), 2.89 (t,J = 5.8 Hz, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.40 (s, 3H), 1.99-1.93 (m, 4H)。MS: m/z 416.1 (M+H+ )。實例 67 下文顯示4,4-二氟-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]吡啶-3-磺醯胺之合成。 步驟 1 向3-溴-6,7-二氫吡唑并[1,5-a]吡啶-4(5H)-酮(500 mg, 2.34 mmol)於DCM (5 mL)中之溶液中添加I2 (58 mg, 0.23 mmol)及丙烷-1,3-二硫醇(276 mg, 2.57 mmol)，隨後將混合物於室溫下攪拌過夜。隨後將反應物分配在DCM (20 mL)與水(20 mL)之間。分離有機層並用DCM (20 mL)萃取水層。將合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥並在真空中濃縮。藉由矽膠管柱(PE/EA = 2/1)純化殘餘物，從而產生白色固體狀3'-溴-6',7'-二氫-5'H-螺[[1,3]二噻烷-2,4'-吡唑并[1,5-a]吡啶] (530 mg，產率：75%)。步驟 2 於-70℃下向1,3-二溴-5,5-二甲基-咪唑啶-2,4-二酮(1.61 g, 5.6 mmol)於DCM (5 mL)中之溶液中添加HF.吡啶(55%, 3.4 mL, 18.6 mmol)及3'-溴-6',7'-二氫-5'H-螺[[1,3]二噻烷-2,4'-吡唑并[1,5-a]吡啶] (430 mg, 1.4 mmol)。於室溫下攪拌1小時後，將反應物分配在DCM (20 mL)與水(20 mL)之間分離有機層並用DCM (20 mL)萃取水層。合併有機層，用鹽水(20 mL)洗滌，經Na2 SO4 乾燥，過濾並在真空中濃縮。藉由矽膠管柱(PE/EA = 5/1)純化殘餘物，從而產生黃色油狀3-溴-4,4-二氟-4,5,6,7-四氫吡唑并[1,5-a]吡啶(260 mg，產率：57%)。MS: m/z 236.9 (M+H+ )。步驟 3 於-78℃下在N2 下向3-溴-4,4-二氟-4,5,6,7-四氫吡唑并[1,5-a]吡啶(0.26 g, 1.1 mmol)於無水THF (5 mL)中之溶液中緩慢添加己烷中之n-BuLi (0.44 mL, 1.1 mmol, 2.5 M)。於此溫度下攪拌20 min後，於此溫度下緩慢添加醚中之ZnCl2 (1.1 mL, 1.1 mmol, 1 M)。移除冷浴並將反應於r.t.下攪拌1 hr。於0℃下向混合物中添加TCPC (0.33 g, 1.1 mmol)並將混合物於r.t.下攪拌1 hr。將反應用飽和NH4 Cl溶液(2 mL)淬滅並分配在水(20 mL)與EA (20 mL)之間。將有機層用鹽水(80 mL)洗滌，經Na2 SO4 乾燥並濃縮，從而產生黃色油狀粗製4,4-二氟-4,5,6,7-四氫吡唑并[1,5-a]吡啶-3-磺酸2,4,6-三氯苯基酯。將粗製物溶解於THF (5 mL)中，並向溶液中添加NH3. H2 O (5 mL)。於60℃下攪拌過夜後，濃縮反應以移除溶劑。將殘餘物用1 N HCl酸化至pH = 5並分配在EA (20 mL)與水(20 mL)之間。分離有機層並用EA (20 mL)萃取水層。合併有機層，用鹽水(30 mL)洗滌，經Na2 SO4 乾燥，過濾並在真空中濃縮。藉由矽膠管柱(PE/EA = 2/1)純化殘餘物，從而產生黃色固體狀4,4-二氟-4,5,6,7-四氫吡唑并[1,5-a]吡啶-3-磺醯胺(50 mg，產率：經2個步驟19%)。MS: m/z 238 (M+H+ )。步驟 4 4,4-二氟-N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-4,5,6,7-四氫吡唑并[1,5-a]吡啶-3-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(26 mg，產率：28%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.65 (brs, 1H), 7.97 (s,1H), 7.94 (s,1H), 6.93 (s, 1H), 4.28 (t,J = 5.6 Hz, 2H), 2.78 (t,J = 6.8 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.50 (重疊,2H), 2.20-2.11 (m,2H), 1.99-1.91 (m,4H)。MS: m/z 437.0 (M+H+ )。實例 68 下文顯示N-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。N-((8-氟-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係使用製法 A 合成以遞送白色固體狀期望產物(210 mg，產率：61%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.51 (brs, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 4.45 (t,J = 5.2 Hz, 2H), 4.11 (t,J = 6.4 Hz, 2H), 2.82 (t,J = 7.6 Hz, 4H), 2.64 (t,J = 6.8 Hz, 4H), 2.22-2.17 (m, 2H) , 2.05-1.98 (m, 4H)。MS: m/z 421.1 (M+H+ )。實例 69 下文顯示N-((8-甲基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於0℃下向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(1 g, 5.78 mmol)於DCM (20 mL)中之溶液中添加NBS (1.03 g, 5.78 mmol)並將混合物於0℃下攪拌2 hr。將反應混合物倒入H2 O (30 mL)中並用EA (50 mL x2)萃取。將合併之EA用鹽水(100 mL)洗滌，經Na2 SO4 乾燥並濃縮至乾燥。藉由矽膠管柱(PE/EA = 50/1)純化殘餘物，從而產生紅色固體狀8-溴-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(838 mg，產率：57%)。1 H NMR (300 MHz, CDCl3 ): δ = 3.48 (brs, 2H), 2.91 (t,J = 7.5 Hz, 4H), 2.81 (t,J = 6.9 Hz, 4H), 2.19-2.06 (m, 4H)。步驟 2 於室溫下向8-溴-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(200 mg, 0.79 mmol)於二噁烷(8 mL)及H2 O (2 mL)中之溶液中添加甲基酸(52 mg, 0.87 mmol)、K2 CO3 (327 mg, 2.37 mmol)及Pd(PPh3 )4 (45 mg, 0.039 mmol)並將其於100℃下在N2 下攪拌過夜。將反應混合物經二氧化矽過濾，且隨後藉由prep-HPLC (NH3 · H2 O)對其進行純化，從而產生白色固體狀8-甲基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(26 mg，產率：18%)。步驟 3 N-((8-甲基-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係如製法 E 中所述合成以遞送白色固體狀期望產物(14 mg，產率：24%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.41 (s, 1H), 7.81 (s, 1H), 7.60 (s, 1H), 4.44 (t,J = 4.8 Hz, 2H), 4.11 (t,J = 5.6 Hz, 2H), 2.74 (t,J = 6.8 Hz, 4H), 2.69-2.58 (m, 4H), 2.21-2.17 (m, 2H), 2.08 (s, 3H), 2.00-1.92 (m, 4H)。MS: m/z 417.0 (M+H+ )。實例 70 下文顯示(R )-((4-氯-2,6-二異丙基苯基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 向2,6-二異丙基-苯基胺(2.4 g, 13.5 mmol)於DMF (20 mL)中之溶液中一次性添加NCS (1.9 g, 14.2 mmol)。於室溫下攪拌16 hr後，將反應混合物傾倒至水(100 mL)中並用EA (50 mL x2)萃取。將合併之有機層用鹽水(50 mL x2)洗滌，經Na2 SO4 乾燥並濃縮。藉由矽膠管柱(PE/EA = 50/1)純化殘餘物，從而產生紅色油狀4-氯-2,6-二異丙基-苯基胺(2.0 g，產率：70%)。步驟 2 (R )-((4-氯-2,6-二異丙基苯基)胺甲醯基)((6-甲氧基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)磺醯基)醯胺係如製法 E 中所述合成以遞送白色固體狀期望產物(50 mg，產率：51%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.38 (s, 1H), 7.33 (s, 1H), 7.00 (s, 2H), 4.49-4.45 (m, 1H), 4.18-4.08 (m, 3H), 4.00-3.90 (m, 1H), 3.34 (s, 3H), 3.20-3.05 (m, 2H), 1.05-1.03 (m, 12H)。MS: m/z 471.0 (M+H+ )。實例 71 下文顯示N-((8-氯-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3- 磺醯胺之合成。將N,N-二甲基吡啶-4-胺(0.657 mmol, 0.080 g)溶解於THF (1.5mL)中且隨後緩慢添加二碳酸二第三丁基酯(0.626 mmol, 0.144 mL)於THF (1.5mL)中之溶液。攪拌幾分鐘後，添加8-氯-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-胺(0.626 mmol, 130 mg)於THF (1mL)中之溶液並將混合物攪拌30 min。同時，將THF (1mL)中之6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(0.626 mmol, 0.145 g)用氫化鈉(0.626 mmol, 0.023 g)處理並攪拌30 min。此時，混合兩種溶液並攪拌18 h。 隨後將反應用飽和NH4 Cl (10mL)淬滅並用EtOAc (10mL)稀釋。分離各層並用EtOAc (10mL)萃取水層。隨後將合併之有機萃取物用水(10mL)洗滌並濃縮。將所得固體懸浮於MeOH (5mL)中，過濾並藉由prep HPLC (10-40% MeCN:10mM aq.NH4 OH)純化。將經純化部分合併並濃縮，從而產生白色固體狀N-((8-氯-1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-6,6-二甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(4 mg, 1.374%)。1 H-NMR (400 MHz；MeOD): δ 7.68 (s, 1H), 4.08 (s, 2H), 3.86 (s, 3H), 2.90-2.87 (m, 4H), 2.80-2.76 (m, 4H), 2.09-2.02 (m, 5H), 1.11 (s, 6H)。
MS: m/z 465.0 (M+H+ )。實例 72 下文顯示N-((2,2-二甲基-2,3-二氫苯并呋喃-7-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。於80℃下將6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(100 mg, 0.492 mmol)溶解於MeOH (4 mL)中。隨後添加甲醇鈉(0.106 g, 0.492 mmol)並將混合物攪拌30 min。隨後蒸發溶劑並添加MeCN (4 mL)中之7-異氰酸基-2,2-二甲基-2,3-二氫苯并呋喃(0.093 g, 0.492 mmol)並將混合物攪拌過夜。此時，過濾反應物並用EtOAc洗滌濾渣並乾燥，從而產生乳膏固體狀N-((2,2-二甲基-2,3-二氫苯并呋喃-7-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(108.5 mg, 56.19 %)。MS: m/z 393 (M+H+ )。實例 73 下文顯示N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-2-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。2-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺係以與6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺相同之方式製備，只是使用適當3-甲基-3-吡唑啉-5-酮作為起始材料。 將2-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(80 mg, 0.368 mmol)、4-異氰酸基-1,2,3,5,6,7-六氫-s二環戊二烯并苯(0.073 g, 0.368 mmol)及氫化鈉(13.595 mg, 0.368 mmol)在DMF (5 mL)中混合並攪拌過夜。隨後用水淬滅反應並過濾白色固體。濃縮濾液並將殘餘物懸浮於丙酮(10 mL)中，過濾並用丙酮洗滌，之後乾燥，從而產生淡褐色固體狀N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-2-甲基-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(51.4 mg, 33.51 %)。MS: m/z 417 (M+H+ )。實例 74 下文顯示N-((4-氰基-2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。於r.t.下向4-胺基-3,5-二異丙基苯甲腈(300 mg, 1.48 mmol)於無水THF (10 mL)中之溶液中添加Et3 N (0.41 mL, 2.97 mmol)，之後添加三光氣(220 mg, 0.74 mmol)。將反應混合物於60℃下加熱1 hr，之後冷卻至r.t.，且分配在EtOAc (30 mL)與水(20 mL)之間。用EtOAc (2 x 10 mL)萃取水相。將合併之有機萃取物用水(20 mL)、鹽水(20 mL)洗滌，經Na2 SO4 乾燥並在減壓下濃縮，從而產生黃色固體(210 mg, 62%)。 將固體(100 mg, 0.44 mmol)溶解於無水DMF (1 mL)中。於r.t.下向此溶液中添加6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(90 mg, 0.44 mmol)，之後添加NaH (60%於礦物油中, 17 mg, 0.44 mmol)。將反應攪拌1 hr，之後添加MeOH (3 mL)。在減壓下移除溶劑並藉由矽膠層析(MeOH/DCM 0至5%)純化所得殘餘物，從而得到白色固體狀N-((4-氰基-2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(36.3 mg, 19%)。MS: m/z 432 (M+H+ )。實例 75 下文顯示N-((4-氯-2,6-二環丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。於r.t.下向4-氯-2,6-二環丙基苯胺(180 mg, 0.87 mmol)於無水THF (10 mL)中之溶液中添加Et3 N (0.24 mL, 1.73 mmol)，之後添加三光氣(130 mg, 0.43 mmol)。將反應混合物於60℃下加熱1 hr，之後冷卻至r.t.，並分配在EtOAc (30 mL)與水(20 mL)之間用EtOAc (2 x 10 mL)萃取水相。將合併之有機萃取物用水(20 mL)、鹽水(20 mL)洗滌，經Na2 SO4 乾燥並在減壓下濃縮，從而產生淺黃色固體(170 mg, 84%)。 將固體(100 mg, 0.49 mmol)溶解於無水DMF (1 mL)中。於r.t.下向此溶液中添加6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(115 mg, 0.49 mmol)，之後添加NaH (60%於礦物油中, 20 mg, 0.49 mmol)。將反應混合物於RT下攪拌1 hr，之後添加MeOH (3 mL)。在減壓下移除溶劑並藉由矽膠層析(MeOH/DCM 0至5%)純化所得殘餘物，從而得到白色固體狀N-((4-氯-2,6-二環丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(37.7 mg, 17%)。MS: m/z 437 (M+H+ )。實例 76 N-((3,5-二環丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成於r.t.下向3,5-二環丙基苯胺(200 mg, 1.15 mmol)於無水THF (10 mL)中之溶液中添加Et3 N (0.27 mL, 2.0 mmol)，之後添加三光氣(120 mg, 0.39 mmol)。將反應攪拌2 hr，之後移除THF。將所得殘餘物懸浮於己烷(50 mL)中，藉由真空過濾移除不溶性白色固體並在減壓下移除己烷，從而產生澄清油。 隨後將獲得之油溶解於無水DMF (2 mL)中。於r.t.下向此溶液中添加6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(80 mg, 0.39 mmol)，之後添加NaH (60%於礦物油中, 20 mg, 0.49 mmol)。將反應混合物攪拌1 hr，之後添加MeOH (5 mL)。在減壓下移除溶劑並藉由矽膠層析(MeOH/DCM 0至10%)純化所得殘餘物，從而得到白色固體狀N-((3,5-二環丙基苯基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(90 mg, 57%)。MS: m/z 403 (M+H+ )。實例 77 下文顯示N-((7-氯-5-環丙基-2,3-二氫-1H-茚-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。於r.t.下向7-氯-5-環丙基-2,3-二氫-1H-茚-4-胺(85 mg, 0.41 mmol)於無水THF (10 mL)中之溶液中添加Et3 N (0.17 mL, 1.2 mmol)，之後添加三光氣(60 mg, 0.20 mmol)。將反應混合物於60℃下加熱1 hr，之後冷卻至r.t.，並分配在EtOAc (30 mL)與水(20 mL)之間。用EtOAc (2 x 10 mL)萃取水相。將合併之有機萃取物用水(20 mL)、鹽水(20 mL)洗滌，經Na2 SO4 乾燥並在減壓下濃縮，從而產生黃色油。 隨後將獲得之油溶解於無水DMF (1 mL)中。於r.t.下向此溶液中添加6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(50 mg, 0.25 mmol)，之後添加NaH (60%於礦物油中, 16 mg, 0.41 mmol)。將反應混合物攪拌1 hr，之後添加MeOH (5 mL)。在減壓下移除溶劑並藉由矽膠層析(MeOH/DCM 0至10%)純化所得殘餘物，從而得到淺黃色固體狀N-((7-氯-5-環丙基-2,3-二氫-1H-茚-4-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(60 mg, 57%)。MS: m/z 437 (M+H+ )。實例 78 下文顯示N-((1,2,3,4-四氫吖啶-9-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺之合成。於r.t.下向1,2,3,4-四氫吖啶-9-胺(200 mg, 1.01 mmol)於無水THF (10 mL)中之溶液中添加Et3 N (0.17 mL, 1.2 mmol)，之後添加三光氣(150 mg, 0.49 mmol)。將反應混合物於60℃下加熱2 hr，之後冷卻至RT。移除THF並將所得殘餘物懸浮於己烷(50 mL)中，藉由真空過濾移除不溶性白色固體並在減壓下移除己烷，從而產生黃色油。 隨後將獲得之油溶解於無水DMF (1 mL)中。於r.t.下向此溶液中添加6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(50 mg, 0.25 mmol)，之後添加NaH (60%於礦物油中, 20 mg, 0.49 mmol)。將反應混合物攪拌1 hr，之後添加MeOH (1 mL)。藉由pre-HPLC (MeCN/水/0.1%甲酸)純化殘餘物，從而得到白色固體狀N-((1,2,3,4-四氫吖啶-9-基)胺甲醯基)-6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-3-磺醯胺(1.8 mg, 2%)。MS: m/z 428 (M+H+ )。實例 79 下文顯示((6-(胺基甲基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉及((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-((2,2,2-三氟乙醯胺基)甲基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成。 步驟 1 ： 將(6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)甲胺(粗製，約1.2 mmol)溶解於TFAA (3 mL)中。將溶液加熱回流3 hr後，利用添加EA (20 mL)及水(10 mL)對其進行淬滅。分離有機層。用EA (10 mL x3)萃取水層。合併有機層並用鹽水(10 mL)洗滌，且經無水Na2 SO4 乾燥。在真空中濃縮溶液。藉由矽膠管柱(PE/EA = 1/1)純化殘餘物，從而產生黃色固體狀N -((6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)甲基)-2,2,2-三氟乙醯胺(140 mg，產率：47%)。MS: m/z 250.2 (M + H+ )。步驟 2 ： 於0℃下向N -((6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)甲基)-2,2,2-三氟乙醯胺(140 mg, 0.56 mmol)於DCM (3 mL)中之溶液中逐滴添加ClSO3 H (0.11 mL, 1.68 mmol)。於室溫下攪拌16 hr後，於0℃下逐滴添加吡啶(0.14 mL, 1.68 mmol)。且隨後於0℃下逐份添加PCl5 (350 mg, 1.68 mmol)。將反應混合物於室溫下攪拌1 hr，倒入冰水(2 mL)中並用EA (10 mL x3)萃取。將合併之有機層用鹽水(10 mL)洗滌，經無水Na2 SO4 乾燥並濃縮，從而產生粗產物，其不經進一步純化即直接用於下一步驟。步驟 3 ： 向6-((2,2,2-三氟乙醯胺基)甲基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-磺醯氯(粗製，約0.56 mmol)於THF (3 mL)中之溶液中添加NH3 .H2 O (3 mL)。於60℃下攪拌2 hr後，將反應混合物濃縮至約1 mL。將殘餘懸浮液用1 M aq.HCl酸化至pH = 3並過濾。藉由反相管柱(MeCN/H2 O)純化濾液，從而產生黃色固體狀2,2,2-三氟-N -((3-胺磺醯基-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)甲基)乙醯胺(120 mg，產率：65%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.58 (s, 1H), 4.51 (dd,J = 11.2, 2.8 Hz, 1H), 4.32-4.23 (m, 2H), 3.96 (dd,J = 12.4, 3.2 Hz, 1H), 3.44 (d,J = 7.2 Hz, 2H), 2.73-2.64 (m, 1H)。步驟 4 ： 向N -((3-胺磺醯基-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)甲基)乙醯胺(60 mg, 0.18 mmol)於DMSO (2 mL)中之懸浮液中添加MeONa (10.7 mg, 0.2 mmol)並將混合物於室溫下攪拌20 min，從而產生鈉鹽懸浮液。在另一燒瓶中，向1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基胺(38 mg, 0.22 mmol)及TEA (54 mg, 0. 54 mmol)於THF (2 mL)中之溶液中一次性添加三光氣(24 mg, 0.80 mmol)並將混合物於室溫下在N2 下攪拌20 min。隨後過濾反應混合物。向上述鈉鹽懸浮液中添加濾液並於室溫下攪拌16 hr。其後，過濾上述懸浮液，藉由反相管柱(MeCN/H2 O)純化濾液，從而產生白色固體狀((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-((2,2,2-三氟乙醯胺基)甲基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉(44 mg，產率：44%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 9.69 (t,J = 5.6 Hz, 1H), 7.53 (brs, 1H), 7.41 (s, 1H), 6.80 (s, 1H), 4.37 (dd,J = 10.8, 2.8 Hz, 1H), 4.19-4.11 (m, 2H), 3.88 (dd,J = 12.0, 7.6 Hz, 1H), 3.30-3.25 (m, 2H), 2.75 (t,J = 7.2 Hz, 4H), 2.66-2.59 (m, 5H), 1.95-1.85 (m, 4H)。MS: m/z 528.1 (M + H+ )。步驟 5: 向((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)((6-((2,2,2-三氟乙醯胺基)甲基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉(7 mg, 0.01 mmol)於DMSO (1 mL)中之溶液中添加NaOH水溶液(0.5 mL, 1 mmol, 2 M)並將混合物於室溫下攪拌48 hr。其後，過濾懸浮液並藉由反相管柱(MeCN/H2 O)純化濾液，從而產生白色固體狀((6-(胺基甲基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)醯胺鈉(4.9 mg，產率：84%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.45 (brs, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 4.37 (dd,J = 10.8, 3.2 Hz, 1H), 4.13-4.02 (m, 2H), 3.82 (dd,J = 12.4, 8.0 Hz, 1H), 2.74 (t,J = 6.8 Hz, 4H), 2.68-2.57 (m, 6H), 2.30-2.12 (m, 1H), 1.94-1.85 (m, 4H)。MS: m/z 432.1 (M + H+ )。實例 80 下文顯示(R )-((4-氟-2,6-二異丙基苯基)胺甲醯基)((6-甲氧基-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺之合成。 步驟 1 在N2 中向2,6-二溴-4-氟苯胺(2.0 g, 7.4 mmol)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧雜硼烷(3.37 g, 20.1 mmol)、Cs2 CO3 (7.23 g, 22.2 mmol)及H2 O (4 mL)於二噁烷(40 mL)中之溶液中添加Pd(dppf)Cl2 (0.54 g, 0.74 mmol)。將反應混合物於100℃下攪拌過夜。在真空中濃縮混合物。藉由矽膠管柱層析(PE/EA = 10/1)純化殘餘物，從而產生褐色油狀4-氟-2,6-二(丙-1-烯-2-基)苯胺(1.10 g, 78%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 6.72 (d,J = 9.6 Hz, 2H), 5.29 (t,J = 1.6 Hz, 2H), 5.01 (d,J = 1.2 Hz, 2H), 4.24 (s, 2H), 2.01 (s, 6H)。步驟 2 向4-氟-2,6-二(丙-1-烯-2-基)苯胺(1.10 g, 5.7 mmol)於MeOH (30 mL)中之溶液中添加Pd/C (0.11 g, 10% wt)。將反應混合物脫氣並用H2 吹掃三次。將其於室溫下在H2 氣球氣氛下攪拌過夜並藉由LCMS監測。過濾混合物。在真空中濃縮濾液，從而產生褐色油狀4-氟-2,6-二異丙基苯胺(1.05 g, 94%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 6.67 (d,J = 10.0 Hz, 2H), 4.44 (brs, 2H), 3.07-3.01 (m, 2H), 1.16-1.10 (m, 12H)。步驟 3 於-5℃下向(R )-6-甲氧基-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-磺醯胺(55 mg, 0.25 mmol)於THF (5 mL)中之溶液中添加MeONa (15 mg, 0.28 mmol)。隨後將反應混合物於-5℃下攪拌30 min。單獨地，於-5℃下向4-氟-2,6-二異丙基苯胺(45 mg, 0.23 mmol)於THF (5 mL)中之溶液中添加三光氣(27 mg, 0.092 mmol)及TEA (47 mg, 0.46 mmol)。隨後將反應混合物於-5℃下攪拌30 min。過濾此反應物並於-5℃下將濾液添加至來自第一步驟之(R )-((6-甲氧基-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉之懸浮液中。將反應於室溫下攪拌過夜。在真空中移除溶劑後，藉由prep-HPLC純化殘餘物，從而產生白色固體狀(R )-((4-氟-2,6-二異丙基苯基)胺甲醯基)((6-甲氧基-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉(28.2 mg, 27%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.65 (s, 1H), 7.57 (s, 1H), 6.91 (d,J = 9.6 Hz, 2H), 4.63 (d,J = 11.6 Hz, 1H), 4.31 (d,J = 11.6 Hz, 1H), 4.22 (d,J = 1.6 Hz, 2H), 4.06 (s, 1H), 3.36 (s, 3H), 2.96-2.86 (m, 2H), 1.05 (s, 12H)。MS: m/z 455.1 (M + H+ )。實例 81 (R )-((4-氟-2,6-二異丙基苯基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉之合成 步驟 1 於-5℃下向(R )-甲基(3-胺磺醯基-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)胺基甲酸第三丁基酯(375 mg, 1.13 mmol)於THF (10 mL)中之溶液中添加MeONa (165 mg, 3.06 mmol)。隨後將反應混合物於-5℃下攪拌30 min。單獨地，於-5℃下向4-氟-2,6-二異丙基苯胺(200 mg, 1.02 mmol)於THF (5 mL)中之溶液中添加三光氣(121 mg, 0.41 mmol)及TEA (0.28 mL, 2.04 mmol)。隨後將反應混合物於-5℃下攪拌30 min並藉由TLC監測。過濾此反應物並於-5℃下將濾液添加至來自第一步驟之(R )-((6-((第三丁氧基羰基)(甲基)胺基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉之懸浮液中。將反應於室溫下攪拌過夜。在真空中移除溶劑後，藉由急速管柱層析純化殘餘物，從而產生黃色固體狀(R )-(3-(N -((4-氟-2,6-二異丙基苯基)胺甲醯基)胺磺醯基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(237 mg, 43%)。步驟 2 向(R )-(3-(N -((4-氟-2,6-二異丙基苯基)胺甲醯基)胺磺醯基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-6-基)(甲基)胺基甲酸第三丁基酯(100 mg, 0.18 mmol)於DCM (2 mL)中之溶液中添加CF3 CO2 H (5 mL)。隨後將反應混合物於室溫下攪拌20 min。於-5℃下將混合物用4 M NaOH水溶液鹼化至pH = 12。在真空中濃縮水層。藉由急速管柱層析純化殘餘物，從而產生黃色固體狀(R )-((4-氟-2,6-二異丙基苯基)胺甲醯基)((6-(甲基胺基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉(23.6 mg, 23%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.67 (s, 1H), 7.57 (s, 1H), 6.92 (d,J = 10.0 Hz, 2H), 4.40-4.28 (m, 2H), 4.22 (dd,J = 12.4, 4.4 Hz, 1H), 3.94 (dd,J = 12.8, 4.4 Hz, 1H), 3.21-3.16 (m, 1H), 2.95-2.85 (m, 2H), 2.34 (s, 3H) 1.09-1.00 (m, 12H)。MS: m/z 454.2 (M + H+ )。實例 82 下文顯示N -((4-氟-2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-磺醯胺之合成。 步驟 1 於-5℃下向6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-磺醯胺(100 mg, 0.45 mmol)於THF (5 mL)中之溶液中添加MeONa (73 mg, 1.35 mmol)及DMSO (1 mL)。隨後將反應混合物於-5℃下攪拌30 min。單獨地，於-5℃下向4-氟-2,6-二異丙基苯胺(100 mg, 0.45 mmol)於THF (5 mL)中之溶液中添加三光氣(53 mg, 0.18 mmol)及TEA (0.13 mL, 0.90 mmol)。隨後將反應混合物於-5℃下攪拌30 min。過濾此反應物並於-5℃下將濾液添加至來自第一步驟之((6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-基)磺醯基)醯胺鈉之懸浮液中。將反應於室溫下攪拌過夜。在真空中移除溶劑後，藉由prep-HPLC純化殘餘物，從而產生白色固體狀N -((4-氟-2,6-二異丙基苯基)胺甲醯基)-6,7-二氫-5H -吡唑并[5,1-b ][1,3]噁嗪-3-磺醯胺(103.5 mg, 54%)。1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.52 (brs, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 6.89 (d,J = 10.0 Hz, 2H), 4.39 (t,J = 4.8 Hz, 2H), 4.08 (t,J = 6.4 Hz, 2H), 3.00-2.90 (m, 2H), 2.24-2.14 (m, 2H), 1.04 (s, 12H)。MS: m/z 424.8 (M + H+ )。生物測試方法 縮寫 PBMC：外周血單核細胞 KC：庫弗氏細胞 FBS：胎牛血清 LPS：脂多醣 NLRP3 活化及抑制分析 使用以下分析中之一些以使用常見發炎體活化刺激物尼日利亞菌素(nigericin)來測定化合物對NLRP3發炎體之抑制活性。生物實例 1 ： 細胞培養 自健康供體之人類外周血新鮮分離由淋巴球(T、B及NK細胞)、單核球及樹突細胞組成之人類外周血單核細胞(PBMC)。經由由iXCells Biotechnologies之IRB批准之供體程式獲得細胞，其中所有供體皆進行了細菌及病毒感染測試。使用聚蔗糖梯度離心自外周血純化細胞。 藉由自由Samsara Sciences死後收穫之肝樣本之梯度分離獲得駐留在狄氏間隙(space of Disse)中之特化之肝巨噬細胞人類庫弗氏細胞(KC)。經由由Samsara Sciences之IRB批准之供體程式獲得細胞，且所有供體經測定對細菌及病毒感染呈陰性。生物實例 2 ： NLRP3 發炎體活化分析 將新鮮或冷凍保藏之PMBC以每孔0.5-1×105 個細胞接種於V底96孔板中，並於37℃、5% CO2 下在具有GlutaMAX補充物、4.5 g/L D-葡萄糖、10%胎牛血清(FBS)、100mM丙酮酸鈉、1%青黴素/鏈黴素、10mM HEPES及0.05mM β-巰基乙醇之RPMI 1640培養基中培育過夜。將新鮮分離或冷凍保藏之KC細胞以0.6-1.5×105 個細胞/孔接種於平底96孔板中，並於37℃、5% CO2 下在具有GlutaMAX補充物、FBS、1%青黴素/鏈黴素及10mM HEPES之RPMI 1640培養基中培育過夜。次日，將細胞用100 ng/mL脂多醣(LPS；Sigma Aldrich)在無FBS之RPMI 1640中初免3小時。在初免步驟後，移除培養基，並在添加NLRP3活化劑之前，將PBMC在不含FBS之培養基中與連續濃度之測試化合物(0.00017 - 10uM)或媒劑(DMSO)一起預培育30分鐘。隨後將細胞用10uM尼日利亞菌素(Sigma Aldrich；InvivoGen)刺激1.5 h。將板以1,500 rpm離心3分鐘以沈澱細胞，並將上清液轉移至新板中用於後續實驗。 細胞介素之量測 / NLRP3 發炎體活性之評價 對於ELISA分析，將細胞接種至96孔板中。在研究後，移除上清液，並根據製造商說明書藉由ELISA在細胞條件培養基中量測成熟IL-1β、IL18及TNFα (Quantikine ELISA, R&D systems)之含量。 結果 下文顯示某些化合物之結果。 生物實例 3 ： CTG (CellTitre-Glo) 分析 使用CellTiter-Glo®分析(Promega, Madison, WI)量測化合物處理之細胞之存活率，該分析量測與孔內活細胞數成正比之細胞之ATP含量。此係用以確立經LPS及尼日利亞菌素刺激且化合物處理之細胞中IL-1β含量之降低並非由於細胞毒性、而是經由發炎體路徑之抑制所致的反篩選。抑制NRLP3發炎體活化之化合物最終藉由阻斷NLRP3介導之細胞焦亡(否則會導致細胞溶解)來增加LPS及尼日利亞菌素刺激之細胞的存活率。生物實例 4 ： TNF-α 藉由HTRF分析(Cisbio, Bedford, MA)量測經LPS及尼日利亞菌素刺激之細胞的TNFα含量。發炎體路徑選擇性化合物不抑制僅依賴於LPS刺激並經由TLR4/NFkB路徑途徑進行之TNFα產生。量測TNFα產生亦用作用以消除干擾HTRF試劑之化合物的技術反篩選。因此，將抑制IL-1β及TNFα含量之化合物分類為對發炎體無選擇性或干擾HTRF讀出。 額外分析 使用以下分析中之一些。生物實例 5 ：人類微粒體穩定性 (Eh) 使用DMSO作為稀釋劑以10 mM之濃度製備測試檢品及陽性對照之原液。隨後將所有原液用70%乙腈稀釋至0.25 mM之工作濃度。此研究中使用之輔因子係NADPH再生系統，其由6.5 mM NADP、16.5 mM G-6-P、3 U/mL G-6-P D構成。淬滅試劑由含有甲苯磺丁脲及心得安(propanolol) (用作內標準品)之乙腈組成。培育混合物含有於100 mM磷酸鉀緩衝液中之0.5 mg/mL肝微粒體蛋白及1 μM檢品/陽性對照。 藉由向300 µL淬滅試劑中添加每一培育混合物之80 µL等分試樣以沈澱蛋白質來製備0分鐘樣品。將樣品渦旋，且隨後加入NADPH再生系統之20 µL等分試樣。藉由向320 µL每一培育混合物中添加80 µL NADPH再生系統來起始反應。400 µL中達到之最終培育條件係：0.5 mg/mL微粒體蛋白、1 µM檢品/陽性對照、1.3 mM NADP、3.3 mM葡萄糖6磷酸鹽、0.6 U/mL葡萄糖6磷酸鹽去氫酶。在輕柔振盪下將混合物在37℃水浴中培育。在10分鐘、30、分鐘、90分鐘，將每一混合物之100 µL等分試樣移除至清潔之96孔板(其含有300 µL淬滅試劑以沈澱蛋白質)，並離心(4000 ×g, 10 min)。將80 μL上清液放入預先添加160 μL超純水之96孔分析板中，且隨後藉由LC-MS/MS進行分析。假設人類肝血液流量為20.7 mL/min/kg，則自量測之活體外清除率計算肝提取率(Eh)值。Eh值＜0.3指示化合物具有有利之代謝穩定性。生物實例 6 ：親脂性： 使用來自ChemAxon之LogD插件計算某些化合物之親脂性(如由logD表示)，如下表中所示。 近年來有多個出版物將候選藥物之臨床成功與其物理性質聯繫起來。舉例而言，親脂性程度可為候選藥物成功之因素。在「Lipophilicity in Drug Discovery」 (Waring, Expert Opinion on Drug Discovery，第5卷，2010 - 第3期第235-248頁，其以引用方式併入本文中)中，作者對磨耗之分析指示，小分子藥物之最佳親脂性(如藉由logD量測)在介於1與3之間之某處。在此範圍之外之化合物之設計可引入不期望傾向性(即ADMET、雜泛性(promiscuity))。在藥物發現之先導物優化過程期間添加非極性原子以鑑別能夠成功通過臨床試驗之品質分子時，應小心。 舉例而言，本文所述吡唑并-噁嗪可提供關於親脂性之有利位置。作為實例，在與具有類似數量之非極性原子之類似物比較時，環狀飽和環避免了約0.7 log單位之clogD升高。另外，噁嗪環異提供具有極性原子之支架，產生1.8之clogD。此可容許利用其他取代基(例如非極性取代基)進一步加工，而不會超出本文所述之理想範圍。結果 某些化合物之結果示於下文及圖1及2中。上文闡述PBMC IL-1β IC50及KC IL-1β IC50。A ＜100nM，B 100nM - 1µM，C 1 - 10µM，D ＞10µM 生物實例 7 ： C57BL/6 小鼠中注射 LPS/ATP 後處理對細胞介素產生之效應 概要 ： 在急性活體內LPS/ATP攻擊模型中探索化合物1及2處理對IL-1β及TNFα細胞介素之NLRP3依賴性釋放的效應。在1.5 mg/kg及5 mg/kg之化合物1及1 mg/kg及2.5 mg/kg之化合物2之單一經口劑量後，在3.5小時之時間點，相對於媒劑處理之動物，來自LPS加ATP攻擊之小鼠之腹膜腔灌洗液中之IL-1β含量降低＞ 98%。在單一經口劑量後，在3.5小時之時間點，相對於媒劑處理之動物，0.5 mg/kg化合物1下，IL-1β釋放減少 ＞ 79%，且在0.25 mg/kg化合物2下，減少＞ 57%。與媒劑處理之動物相比，任何組中之TNFα含量皆無顯著變化。 化合物1：化合物2：化合物3：化合物4：化合物5： 研究目標 ： 本研究之目的係測定雌性C57BL/6小鼠中注射LPS/ATP後化合物1及2處理對細胞介素產生的效應。實驗設計及程序： 關鍵研究參數示於表1中。 在研究開始之前使小鼠適應設施至少7天。 在第-1天，將小鼠稱重並根據表2(參見下文)以平衡方式分配至組，以在研究開始時在各組之間達成類似之平均體重。 *針對鹽含量進行校正 在-1小時，所有小鼠皆接受處理或媒劑之單一劑量。 在0小時，所有小鼠皆腹腔內接受1 μg於0.5 ml PBS中之超純脂多醣(LPS, lnvivoGen, San Diego, CA)。 在第2小時(LPS注射後2小時)，向所有小鼠腹膜內注射0.5 ml 80 mM ATP二鈉鹽(Sigma，在注射前將pH調節至7.2)。 在第2.5小時(ATP注射後30分鐘及化合物投藥後3.5小時)，經由眼眶後出血將所有小鼠之血液採集至K2 EDTA管中，並製備血漿並在80℃下儲存。選擇在此研究完成7天內將樣品運送至客戶或客戶之供應商。 在採集血液後立即使每一小鼠安樂死，將腹膜腔用3 ml含有25U/ml肝素鈉鹽、蛋白酶抑制劑混合物(complete™ ULTRA Tablets, Sigma, Roche)及10%FBS之冰冷PBS灌洗。採集約1 ml灌洗液，旋轉以移除細胞並將上清液於-80℃下儲存。 化合物1之媒劑係PBS，且化合物2之媒劑係0.5%甲基纖維素。在4℃下儲存化合物粉末。所有化合物皆新鮮製備。稱出化合物並首先用研缽及研杵研磨，隨後與少量媒劑一起研磨。隨後用媒劑反覆沖洗研缽以移除所有物質並達成正確濃度。將最終溶液渦旋以產生均質混合物。細胞介素分析： 根據製造商之方案，使用Becton Dickinson (Franklin Lakes, NJ) CBA分析套組測定腹膜灌洗液樣品中之小鼠IL-1β及TNFα濃度。對每一樣品實施單一分析。統計分析 ： 使用Student t-測試比較細胞介素之濃度。結果 ： 在LPS/ATP注射模型中評估化合物1及化合物2處理對IL-1β細胞介素產生之效應。向雌性C57BL/6小鼠經口投用0.5 mg/kg、1.5 mg/kg及5 mg/kg之化合物1或0.25 mg/kg、1 mg/kg及2.5 mg/kg之化合物2，且使用Becton Dickinson CBA分析套組測定IL-lβ之相對量(pg/ml)。在1.5 mg/kg及5 mg/kg之化合物1及1 mg/kg及2.5 mg/kg之化合物2之單一經口劑量後，在3.5小時之時間點，相對於媒劑處理之動物，來自LPS加ATP攻擊之小鼠之腹膜腔灌洗液中之IL-1β含量降低＞ 98% (表3及4，圖3)。 在單一經口劑量後，在3.5小時之時間點，相對於媒劑處理之動物，0.5 mg/kg化合物1下，IL-1β釋放減少＞ 79%，且在0.25 mg/kg化合物2下，減少＞ 57%。與媒劑處理之動物相比，任何組中之TNFα含量皆無顯著變化(表3及4，圖4)。 在LPS/ATP注射模型中評估化合物3處理對IL-1β細胞介素產生之效應。向雌性C57BL/6小鼠經口投用0.25 mg/kg、1 mg/kg及2.5 mg/kg之化合物3，且使用Becton Dickinson CBA分析套組測定IL-lβ之相對量(pg/ml)。在1 mg/kg及2.5 mg/kg之化合物2之單一經口劑量後，在3.5小時之時間點，相對於媒劑處理之動物，來自LPS加ATP攻擊之小鼠之腹膜腔灌洗液中之IL-1β含量降低＞ 96% (表5，圖5)。 結論 ： 在急性活體內LPS/ATP攻擊模型中探索化合物1及化合物2處理對IL-lβ細胞介素之NLRP3依賴性釋放的效應。在1.5 mg/kg及5 mg/kg之化合物1及1 mg/kg及2.5 mg/kg之化合物2之單一經口劑量後，在3.5小時之時間點，相對於媒劑處理之動物，來自LPS加ATP攻擊之小鼠之腹膜腔灌洗液中之IL-1β含量降低＞ 98%。在單一經口劑量後，在3.5小時之時間點，相對於媒劑處理之動物，0.5 mg/kg化合物1下，IL-1β釋放減少＞79%，且在0.25 mg/kg化合物2下，減少＞ 57%。與媒劑處理之動物相比，任何組中之TNFα含量皆無顯著變化。生物實例 8 ：半胱天冬酶 1 活化之抑制 材料及方法 細胞培養 自16隻Black 6小鼠之新鮮收穫之小鼠骨收集骨髓細胞，各自來自4個骨(2個脛骨及2個股骨)。在完全BMDM培養基中新鮮遞送骨：RPMI 1640培養基，GlutaMAX™補充物、1%非必需胺基酸、1%青黴素/鏈黴素、10 mM HEPES、0.05 mM β-ME、20 ng/ml GM-CSF及10% FBS。用剪刀切割掉頂部及底部，且使用25G針自每一骨用完全BMDM培養基仔細洗滌細胞。使細胞通過100 μm細胞過濾器，之後以250g離心。根據製造商之說明使用EasySep小鼠單核球分離套組(StemCell Technologies)經由磁性負向選擇來分離CD14+ 細胞。使約2 ml細胞運行3個獨立之純化程序。細胞總數約為12.7百萬。將CD14+ 細胞以25,000個細胞/孔接種至96孔板中。每3天更換完全BMDM培養基。在接種後第9天實施實驗。發炎體活化 將骨髓源巨噬細胞(BMDM)與指定濃度之DMSO或化合物預培育30分鐘，之後用100 ng/ml之LPS刺激。將細胞於37℃、5%CO2 環境下培育3小時。隨後進一步用10 μM尼日利亞菌素刺激細胞，且在37℃、5%CO2 下培育90分鐘。在培育時段結束時收集上清液並分析細胞介素。收穫細胞用於西方墨點分析或使用CellTiter-Glo (Promega)測試存活率。西方墨點法 藉由用50 μl 4x NuPAGE LDS樣品樣品緩衝液(Fisher) + 5% β-巰基乙醇原位溶解細胞來製備來自96孔板之細胞樣品。將板放置於700 rpm之板振盪器上1小時，且隨後超音波處理10分鐘。將細胞溶解物轉移至PCR板並加熱至95℃並保持5 min。使樣品在NuPAGE Bis-Tris凝膠(Fisher)上運行並使用iBlot 2系統(Fisher)轉移至PVDF膜。將PVDF膜在Azure Blot洗滌緩衝液(Azure Biosystems)+ 5%低脂奶粉中封阻至少5 min。用以下一級抗體探測膜：促-半胱天冬酶-1 + p10 + p12 [EPR16883] (Abcam)、β-肌動蛋白(Sigma)、NLRP3 [Cryo-2] (Adipogen)，所有抗體培育皆係在Azure Blot洗滌緩衝液+ 5%低脂奶粉中實施。二級抗體係購自Azure Biosystems。每次抗體與Azure Blot洗滌緩衝液一起培育後，將膜洗滌至少3x5分鐘。用Azure c300成像儀(Azure Biosystems)使膜成像。結果 西方墨點法 先後經LPS及尼日利亞菌素刺激BMDM會引起NLRP3發炎體之活化，其進而起始促-半胱天冬酶-1活化。在自動催化裂解期間，p45促-半胱天冬酶裂解成p10及p20片段。附於西方墨點上之p45帶之強度降低及p10帶之出現指示在LPS及尼日利亞菌素刺激時成功之促-半胱天冬酶-1活化。在10 μM化合物1、4及2存在下，阻斷促-半胱天冬酶-1之活化，如由完整p45帶及缺乏p10帶所指示(圖6)。生物實例 9 ： 小鼠中之藥物動力學 靜脈內投用溶液係以1 mg/kg投與，且係藉由將檢品溶解至下文所示之調配物中來製備。經口投用懸浮液係以10 mg/kg投與，且係藉由將檢品溶解於下文所示之調配物中來製備。將血樣收集至含有K2EDTA或肝素鈉之管中，且在收集之後立即及在處理期間在冰塊或濕冰上保持冷凍。離心後，將所得血漿樣品儲存於-80℃下之冰箱中直至分析樣品。在介於0至24小時範圍內之時間點使用標準生物分析方法量測血漿中之化合物濃度後測定藥物動力學參數。 化合物A：化合物B：化合物C：化合物D：化合物E： 等效內容 儘管已經結合上述具體實施例闡述了本發明，但彼等熟習此項技術者將明瞭其許多替代方案、修改形式及其他變化形式。所有該等替代方案、修改形式及變化形式皆意欲在本發明之精神及範疇內。 Cross-reference to related applications This application claims the benefits of US Provisional Application No. 62 / 449,431, filed on January 23, 2017, and US Provisional Application No. 62 / 492,813, filed on May 1, 2017. These applications The entire contents of the entire contents are incorporated herein by reference. Unless otherwise indicated, the following terms as used above and throughout this disclosure should be understood to have the following meanings: If a term is lost, the term will be used as known to those skilled in the art. As used herein, the terms "including," "including," and "including" are used in their open, non-limiting sense. The article "a (an and an)" used in this disclosure refers to one or more of the grammatical recipients of the article (that is, to at least one). For example, "element" means one element or more than one element. Unless otherwise indicated, the term "and / or" used in this disclosure means "and" or "or". In order to provide a more concise explanation, some quantitative expressions given herein are not limited by the term "about". It should be understood that, whether or not the term "about" is explicitly used, each quantity given herein is intended to refer to the actual value given, and because of the experimental and / or measurement conditions of the given value, it is also intended to refer to the given value. The approximate value of the value can be reasonably inferred based on the general technology in the industry, including equivalents and approximate values. Whenever a yield is given as a percentage, it refers to the maximum amount that the mass of the entity giving the yield can be obtained relative to the same entity under specific stoichiometric conditions. Unless otherwise indicated, concentrations given as percentages refer to mass ratios. A "patient" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. "Patient" includes both humans and animals. The term "inhibitor" refers to a molecule, such as a compound, drug, enzyme, or hormone, that blocks or otherwise interferes with a particular biological activity. The term "effective amount" or "therapeutically effective amount" when used in combination with a compound refers to an amount of the compound sufficient to provide the desired biological result. The result may be reduction and / or alleviation of the signs, symptoms or causes of the disease or any other desired change in the biological system. For example, for therapeutic use, an "effective amount" is the amount of a composition comprising a compound disclosed herein that is required for clinically significant reduction in a disease. The appropriate "effective amount" in any individual case can be determined by one skilled in the art using routine experimentation. Therefore, the expression "effective amount" generally refers to an amount in which the active substance has a therapeutic effect. In this case, the active substance is an inhibitor of the inflamed body. The term "treat or treatment" as used herein is synonymous with the term "prevention" and is intended to indicate a delay in the occurrence of a disease, prevent the occurrence of a disease, and / or reduce the severity of such symptoms that will or are expected to occur. As such, these terms include improving symptoms of an existing disease, preventing additional symptoms, improving or preventing the underlying cause of symptoms, inhibiting a condition or disease, such as blocking the onset of the disease or disease, alleviating the condition or disease, making the condition or disease subside, alleviating the cause A condition caused by a disease or disorder, or the termination or alleviation of symptoms of a disease or disorder. Unless otherwise indicated, the term "disorder" as used in this disclosure means the term disease, condition, or disease and is used interchangeably therewith. By using the terms "pharmaceutically acceptable" or "pharmacologically acceptable" it is intended to mean a substance that is not biologically or otherwise undesirable-the material can be administered to an individual without causing any substantially undesirable organism The chemical effect or interacts in a harmful manner with any component of the composition containing it. The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents, and means involved in carrying or transmitting a medicinal agent from one organ or part of an individual's body to another organ or A portion of the material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Excipients should be selected based on the compatibility and release profile properties of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like. The term "pharmaceutically compatible carrier material" may include, for example, acacia gum, gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soy Lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium lactate stearate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and the like. See (for example) Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975. The term "subject" as used herein encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any mammalian member: humans; non-human primates, such as chimpanzees and other apes and monkeys; agricultural animals, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits , Dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention, the mammal is a human. The invention also includes "prodrugs" of the compounds. The term "prodrug" means a compound that can be metabolized (eg, by hydrolysis) in vivo into the disclosed compound or active ingredient. Prodrugs can be prepared by techniques known to those skilled in the art. These techniques generally modify the appropriate functional groups in a given compound, such as hydroxyl, amine, carboxyl, and other groups. However, these modified functional groups are regenerated into the original functional groups by conventional manipulation or in vivo. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N , N-dimethylaminocarbonyl), amidoamine (eg, trifluoroethylamidoamino, ethylamidoamino and the like) and the like. Since prodrugs are known to enhance many desirable qualities of medicine (such as solubility, bioavailability, manufacturing, transportation, pharmacodynamics, etc.), the compounds of the invention can be delivered in prodrug form. For example, even when the parent drug is not bioavailable, the prodrug can be administered orally for bioavailability. Accordingly, the invention is intended to encompass prodrugs of the compounds claimed herein, methods of their delivery, and compositions containing them. Generally speaking, prodrugs are derivatives of the drug itself that are converted or metabolized into physiologically active substances after administration. Transformation may be spontaneous, such as hydrolysis in a physiological environment, or may be enzyme-catalyzed. Prodrugs can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, esterified, alkylated, dealkylated, tritiated, dephosphorylated, phosphorylated, and / or rezoned A compound that is phosphorylated to produce an active compound. The term "IC" as used herein50 "" Means a concentration that inhibits a measurable activity, phenotype, or response (eg, the growth or proliferation of cells such as tumor cells) by 50%. IC50 Values can be estimated from appropriate dose-response curves, for example by eye or by using appropriate curve fitting or statistical software. More accurately, IC50 Values can be determined using non-linear regression analysis. The term "administered, administration, or administration" as used in this disclosure refers to the direct administration of the disclosed compound or the pharmaceutically acceptable salt or composition of the disclosed compound to an individual, or to the individual. The compound or a pharmaceutically acceptable salt or prodrug derivative or analog of the compound can be obtained by contacting the subject in need of treatment with the compound or otherwise exposing the subject to the compound. An equivalent amount of an active compound is formed in the body of the individual (including animals). As used herein, "alkyl" means a straight or branched saturated chain having 1 to 10 carbon atoms. Representative saturated alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl- 1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- Methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, third butyl, n-pentyl, Isoamyl, neopentyl, n-hexyl and the like, as well as longer alkyls, such as heptyl and octyl and the like. The alkyl group may be unsubstituted or substituted. Alkyl groups containing 3 or more carbon atoms may be straight or branched. "Lower alkyl" as used herein means an alkyl group having 1 to 6 carbon atoms. As used herein, "alkenyl" includes unbranched or branched hydrocarbon chains containing 2 to 12 carbon atoms. "Alkenyl" contains at least one double bond. An alkenyl double bond may be uncoupled or coupled to another unsaturated group. Examples of alkenyl include, but are not limited to, ethylalkenyl, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2 -Ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butene) -pentenyl and the like. Alkenyl may be unsubstituted or substituted. Alkenyl as defined herein may also be branched or linear. "Alkynyl" as used herein includes unbranched or branched unsaturated hydrocarbon chains containing 2 to 12 carbon atoms. An "alkynyl" contains at least one triple bond. The triple bond of the alkynyl group may be uncoupled or coupled to another unsaturated group. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl 2-pentynyl, 4-butyl-2-hexynyl and the like. An alkynyl can be unsubstituted or substituted. The term "hydroxyl or hydroxy" means an OH group; as used herein, the term "alkoxy" refers to a straight or branched chain containing 1 to 12 carbon atoms in the chain and containing a terminal "O" Saturated hydrocarbon, ie -O (alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tertiary butoxy, or pentoxy. It should also be noted that it is assumed that any carbon atoms and heteroatoms having unsaturated valences in the text descriptions, schemes, examples and tables herein have a sufficient number of hydrogen atoms to saturate the valences. As used herein, reference to hydrogen may also refer to deuterium substitution, if desired. The term "deuterium" as used herein means a stable isotope of hydrogen having an odd number of protons and neutrons. The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine. The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, which is substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like. The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like. The term "cyano" as used herein means a substituent bonded to a nitrogen atom through a triple bond carbon atom, that is,. The term "amine group" as used herein means a substituent containing at least one nitrogen atom. Specifically, NH2 , -NH (alkyl) or alkylamino, -N (alkyl)2 Or dialkylamino, amidine, formamidine, urea, and sulfamidine substituents are included in the term "amine". Unless otherwise explicitly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If two aromatic rings (bicyclic rings, etc.) are contained, the aromatic rings of the aryl group may be joined (for example, biphenyl) or fused (for example, naphthyl) at a single point. An aryl group may optionally be substituted with one or more substituents (eg, 1 to 5 substituents) at any point of attachment. The substituent itself may be substituted as appropriate. Furthermore, when containing two fused rings, an aryl group as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems for these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthryl, dihydroindenyl, indenyl, tetrahydronaphthyl , Tetrahydrobenzoannulenyl, and the like. Unless specifically defined otherwise, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group of 5 to 18 ring atoms or as many as one or more ring heteroatoms selected from N, O, or S Ring aromatic group, the remaining ring atoms are C. Heteroaryl, as defined herein, also means a bicyclic heteroaromatic group in which the heteroatom is selected from N, O or S. Aromatic groups are optionally substituted independently with one or more substituents described herein. The substituent itself may be substituted as appropriate. Examples include, but are not limited to, benzothiophene, furyl, thienyl, pyrrolyl, pyridyl, pyrazinyl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, Oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, thieno [3,2-b] Thiophene, triazolyl, triazinyl, imidazo [1,2-b] pyrazolyl, furano [2,3-c] pyridyl, imidazo [1,2-a] pyridyl, indazolyl , Pyrrolo [2,3-c] pyridyl, pyrrolo [3,2-c] pyridyl, pyrazolo [3,4-c] pyridyl, benzimidazolyl, thieno [3,2- c] pyridyl, thieno [2,3-c] pyridyl, thieno [2,3-b] pyridyl, benzothiazolyl, indolyl, indolyl, indololinone, di Hydrobenzothienyl, dihydrobenzofuranyl, benzofuran, alkyl, sulfanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxyl, quinolinyl, Isoquinolinyl, 1,6-naphthyridinyl, benzo [de] isoquinolinyl, pyrido [4,3-b] [1,6] naphthyridinyl, thieno [2,3-b] Pyrazinyl, quinazolinyl, tetrazole [1,5-a] pyridyl, [1,2,4] triazolo [4,3-a] pyridyl, isoindolyl, pyrrolo [2,3-b] pyridyl, pyrrolo [ 3,4-b] pyridyl, pyrrolo [3,2-b] pyridyl, imidazo [5,4-b] pyridyl, pyrrolo [1,2-a] pyrimidinyl, tetrahydropyrrolo [ 1,2-a] pyrimidinyl, 3,4-dihydro-2H-1λ2 -Pyrrolo [2,1-b] pyrimidine, dibenzo [b, d] thiophene, pyridin-2-one, furano [3,2-c] pyridyl, furano [2,3-c] pyridine , 1H-pyrido [3,4-b] [1,4] thiazinyl, benzoxazolyl, benzoisoxazolyl, furano [2,3-b] pyridyl, benzothiophene , 1,5-naphthyridinyl, furano [3,2-b] pyridine, [1,2,4] triazolo [1,5-a] pyridyl, benzo [1,2,3] Triazolyl, imidazo [1,2-a] pyrimidinyl, [1,2,4] triazolo [4,3-b] pyrazinyl, benzo [c] [1,2,5] thio Diazolyl, benzo [c] [1,2,5] oxadiazole, 1,3-dihydro-2H-benzo [d] imidazol-2-one, 3,4-dihydro-2H-pyridine Zolo [1,5-b] [1,2] oxazinyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridyl, thiazolo [5,4-d] Thiazolyl, imidazo [2,1-b] [1,3,4] thiadiazolyl, thieno [2,3-b] pyrrolyl, 3H-indolyl and derivatives thereof. Furthermore, when containing two fused rings, a heteroaryl group, as defined herein, may have an unsaturated or partially saturated ring fused to a fully saturated ring. The term "cycloalkyl" as used herein refers to a saturated or partially saturated, monocyclic, fused or spiro polycyclic carbocyclic ring having 3 to 18 carbon atoms per ring. A cycloalkyl ring or carbocyclic ring may optionally be substituted at any point of attachment by one or more substituents (eg, 1 to 5 substituents). The substituent itself may be substituted as appropriate. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, bicyclo [2.2.2 ] Octyl, bicyclo [2.2.2] octenyl, decahydronaphthyl, octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohex-1,4-dienyl, ring Hex-1,3-dienyl, 1,2,3,4-tetrahydronaphthyl, octahydropentenyl, 3a, 4,5,6,7,7a-hexahydro-1H-indenyl, 1 , 2,3,3a-tetrahydropentenyl, bicyclo [3.1.0] hexyl, bicyclo [2.1.0] pentyl, spiro [3.3] heptyl, bicyclo [2.2.1] heptyl, di Ring [2.2.1] hept-2-enyl, bicyclo [2.2.2] octyl, 6-methylbicyclo [3.1.1] heptyl, 2,6,6-trimethylbicyclo [3.1 .1] heptyl and its derivatives. The term "cycloalkenyl" as used herein refers to a partially saturated, monocyclic, fused or spiro polycyclic carbocyclic ring having 3 to 18 carbon atoms per ring and containing at least one double bond. Cycloalkenyl may optionally be substituted at any point of attachment by one or more substituents (eg, 1 to 5 substituents). The substituent itself may be substituted as appropriate. The term "heterocycloalkyl" or "heterocyclyl" as used herein refers to a saturated or partially unsaturated and non-aromatic monocyclic or fused or spiro, polycyclic ring structure of 4 to 18 atoms, such atoms Non-localized π-electrons (aromatic) containing carbon and heteroatoms derived from oxygen, nitrogen, or sulfur, and no ring carbon or heteroatoms in common. A heterocycloalkyl or heterocyclyl ring structure may be substituted with one or more substituents. The substituent itself may be substituted as appropriate. Examples of heterocycloalkyl or heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazoline, oxazolyl, thiazoline, Thiazolyl, pyranyl, thianyl, tetrahydropyranyl, dioxalinyl, hexahydropyridyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, Thiomorpholinyl S-dioxide, hexahydropyrazinyl, azepine, oxepinyl, diazepine, tropanyl, homotropyl, dihydro Thiophene-2 (3H) -keto, tetrahydrothiophene 1,1-dioxide, 2,5-dihydro-1H-pyrrolyl, imidazol-2-one, pyrrolidin-2-one, dihydrofuran -2 (3H) -one, 1,3-dioxolane-2-one, isothiazolidine 1,1-dioxide, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro Oxazolyl, epoxyethyl, pyrazolidinyl, 4H-1,4-thiazinyl, thiomorpholinyl, 1,2,3,4-tetrahydropyridyl, 1,2,3,4- Tetrahydropyrazinyl, 1,3-oxazinan-2-one, tetrahydro-2H-thiane 1,1-dioxide, 7-oxabicyclo [2.2.1] heptyl, 1,2 -Thioazacycloheptane 1,1-dioxide, octahydro-2H-quinazinyl, 1,3-diaza Bicyclo [2.2.2] octyl, 2,3-dihydrobenzo [b] [1,4] dioxane, 3-azabicyclo [3.2.1] octyl, 8-nitrogen Heterospiro [4.5] decane, 8-oxa-3-azabicyclo [3.2.1] octyl, 2-azabicyclo [2.2.1] heptane, 2,8-diazaspiro [ 5.5] Undecyl, 2-azaspiro [5.5] undecyl, 3-azaspiro [5.5] undecyl, decahydroisoquinolinyl, 1-oxa-8-azaspiro [4.5] decyl, 8-azabicyclo [3.2.1] octyl, 1,4'-dihexahydropyridyl, azacycloheptyl, 8-oxa-3-azabicyclo [ 3.2.1] octyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridine , 1,4-diazacycloheptyl, phenoxathial, benzo [d] [1,3] dioxolenyl, 2,3-dihydrobenzofuranyl, 2, 3-dihydrobenzo [b] [1,4] dioxane, 4- (hexahydropyridin-4-yl) morpholinyl, 3-azaspiro [5.5] undecyl, Decahydroquinolinyl, hexahydropyrazin-2-one, 1- (pyrrolidin-2-ylmethyl) pyrrolidinyl, 1,3'-bipyrrolidinyl, and 6,7,8,9-tetra Hydrogen-1H, 5H-pyrazolo [1,2-a] [1,2] diazepine. Numerical ranges as used herein are intended to include consecutive integers. For example, the range represented as "0 to 5" would include 0, 1, 2, 3, 4 and 5. The term "substituted" as used herein means that a specified group or moiety carries one or more suitable substituents, wherein a substituent may be attached to the specified group or moiety at one or more positions. For example, a cycloalkyl substituted aryl group may indicate that a cycloalkyl group is connected to one atom of the aryl group using a bond or by condensing with the aryl group and sharing two or more common atoms. The term "unsubstituted" as used herein means that the specified group is unsubstituted. The term "optionally substituted" is understood to mean that a given chemical moiety (eg, an alkyl group) can (but need not) be bonded to other substituents (eg, heteroatoms). For example, optionally substituted alkyls can be fully saturated alkyl chains (ie, pure hydrocarbons). Alternatively, the same optionally substituted alkyl group may have a substituent other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for optional substitution of the groups include, but are not limited to, pendant oxy, -halogen, C1 -C6 Alkyl, C1 -C6 Alkoxy, C1 -C6 Haloalkyl, C1 -C6 Haloalkoxy, -OC1 -C6 Alkenyl, -OC1 -C6 Alkynyl, -C1 -C6 Alkenyl, -C1 -C6 Alkynyl, -OH, CN (cyano), -CH2 CN, -OP (O) (OH)2 , -C (O) OH, -OC (O) C1 -C6 Alkyl, -C (O) C1 -C6 Alkyl, -C (O) -C0 -C6 Alkenyl-cycloalkyl, -C (O) -C0 -C6 Alkenyl-heterocycloalkyl, -C (O) -C0 -C6 Alkenyl-aryl, -C (O) -C0 -C6 Alkenyl-heteroaryl, -OC (O) OC1 -C6 Alkyl, NH2 , NH (C1 -C6 Alkyl), N (C1 -C6 alkyl)2 , -C (O) NH2 , -C (O) NH (C1 -C6 Alkyl), -C (O) N (C1 -C6 alkyl)2 , -C (O) NH cycloalkyl, -C (O) N (C1 -C6 Alkyl) cycloalkyl, -C (O) NH heterocycloalkyl, -C (O) N (C1 -C6 Alkyl) heterocycloalkyl, -C (O) NHaryl, -C (O) N (C1 -C6 Alkyl) aryl, -C (O) NH heteroaryl, -C (O) N (C1 -C6 Alkyl) heteroaryl, -S (O)2 -C1 -C6 Alkyl, -S (O)2 -C1 -C6 Haloalkyl, -S (O)2 -Cycloalkyl, -S (O)2 -Heterocycloalkyl, -S (O)2 -Aryl, -S (O)2 -Heteroaryl-C0 -C6 Alkenyl-S (O)2 NH2 , -S (O)2 NHC1 -C6 Alkyl, -S (O)2 N (C1 -C6 alkyl)2 , -S (O)2 NH cycloalkyl, -S (O)2 NH heterocycloalkyl, -S (O)2 NH aryl, -S (O)2 NH heteroaryl, -NHS (O)2 C1 -C6 Alkyl, -N (C1 -C6 Alkyl) S (O)2 (C1 -C6 Alkyl), -NHS (O)2 Aryl, -N (C1 -C6 Alkyl) S (O)2 Aryl, -NHS (O)2 Heteroaryl, -N (C1 -C6 Alkyl) S (O)2 Heteroaryl, -NHS (O)2 Cycloalkyl, -N (C1 -C6 Alkyl) S (O)2 Cycloalkyl, -NHS (O)2 Heterocycloalkyl, -N (C1 -C6 Alkyl) S (O)2 Heterocycloalkyl, -N (C1 -C6 Alkyl) S (O)2 Aryl, -C0 -C6 Alkenyl-aryl, -C0 -C6 Alkenyl-heteroaryl, -C0 -C6 Alkenyl-cycloalkyl, -C0 -C6 Alkyl alkenyl-heterocycloalkyl, -O-aryl, -NH-aryl, and N (C1 -C6 Alkyl) aryl. The substituent itself may be substituted as appropriate. When displaying a polyfunctional moiety, the attachment point to the core is indicated by a line, for example, (cycloalkyloxy) alkyl- refers to the attachment point of an alkyl system to the core, and the cycloalkyl is attached via an oxy group Connected to alkyl. "Substituted as appropriate" also means "substituted" or "unsubstituted", which has the above meaning. The term "oxa" as used herein refers to a "-O-" group. The term "lateral oxygen" as used herein refers to a "= O" group. The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of the present invention, these solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Among them, a solvate of an aqueous solvent molecule is generally called a hydrate. Hydrates include compositions containing stoichiometric amounts of water, and compositions containing variable amounts of water. The term "salt" as used herein means acidic salts formed using inorganic and / or organic acids, and basic salts formed using inorganic and / or organic bases. In addition, when the compound of the formula contains both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), a zwitterion ("internal salt") can be formed and is included as described herein The term "salt" is used. Pharmaceutically acceptable (ie, non-toxic physiologically acceptable) salts are preferred, but other salts are also useful. For example, a salt of a compound of formula can be formed by reacting the compound of formula with a certain amount (e.g., 1 equivalent) of an acid or base in a medium such as a salt-precipitable medium or in an aqueous medium, followed by lyophilization. In another embodiment of the present invention, the compound of formula (I) is a mirror image isomer. In some embodiments, the compounds are (S )-Mirror image isomer. In other embodiments, the compounds are (R )-Mirror image isomer. In other embodiments, the compound of formula (I) may be a (+) or (-) mirror isomer. It is understood that all isomeric forms, including mixtures thereof, are encompassed within the present invention. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The invention is also intended to include all tautomeric forms. Compounds of various formulas and their salts, solvates, esters, and prodrugs can exist in their tautomeric forms (for example, as amidamine or imino ether). All such tautomeric forms are covered herein as part of the invention. Compounds of various formulae may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the various formulae and their mixtures (including racemic mixtures) form part of the invention. In addition, the present invention encompasses all geometric and positional isomers. For example, if compounds of various formulae incorporate double bonds or fused rings, both cis- and trans-forms and mixtures are encompassed within the scope of the invention. Each compound disclosed herein includes all mirror isomers that conform to the general structure of the compound. The compounds may be in racemic or mirror-isomeric pure form or any other form in stereochemistry. The results of the analysis may reflect data collected for the racemic form, the mirror-isomeric pure form, or any other form of stereochemistry. Non-mirromeric isomers can be separated into their individual non-mirromeric isomers based on their physicochemical differences by methods familiar to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to non-enantiomers by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher (R) chloride). Mixtures, separate the non-image isomers and convert (eg, hydrolyze) the individual non-image isomers to the corresponding pure image isomers. Similarly, some compounds of the various formulas may be atropisomers (such as substituted diaryl groups) and are considered a part of the present invention. Mirror isomers can also be separated by using a chiral HPLC column. The compounds of formula (I) may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the invention. For example, all keto-enol and imine-enamine forms of the compound are also included in the present invention. All stereoisomers (e.g., geometric isomers, optics) of the compounds of the invention (including their salts, solvates, esters, and prodrugs of these compounds and salts, solvates, and esters of these prodrugs) Isomers and the like), such as those which exist due to asymmetric carbon atoms on each substituent, including mirror-isomeric forms (which can exist even without asymmetric carbons), rotationally isomeric forms, atropism Both isomers and non-mirror isomeric forms are included in the scope of the present invention, and positional isomers (for example, 4-pyridyl and 3-pyridyl) are also included in the scope of the present invention. (For example, if a compound of various formulas incorporates a double bond or a fused ring, both cis- and trans-forms and mixtures are encompassed within the scope of the invention. For example, all keto-enol and sub- Amine-enamine forms are also included in the present invention.) Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may be, for example, a mixture of racemates, or may be Mix with all other stereoisomers or other selected stereoisomers. The chiral center of the present invention may have an S or R configuration, as defined by IUPAC 1974 Recommendations. The present invention also encompasses the isotope-labeled compounds of the present invention, which are the same as those described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that found in nature. Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as2 H (or D),3 H,13 C,14 C,15 N,18 O,17 O,31 P,32 P,35 S,18 F and36 Cl. Certain isotopically labeled compounds of various formulas (e.g., via3 H and14 C-labeled ones) can be used in the analysis of compounds and / or tissue distribution. Tritiated (i.e.3 H) and carbon-14 (i.e.14 C) Isotopes are particularly preferred because of their ease of preparation and detectability. In addition, using materials such as deuterium (i.e.2 H) Substituting heavier isotopes, etc., may provide certain therapeutic advantages (such as increased half-life in vivo or reduced dose need) due to stronger metabolic stability, and may therefore be better in some cases. Isotopically labeled compounds of various formulae can generally be prepared by following procedures similar to those disclosed in the schemes and / or the examples below, by replacing unisotopically labeled reagents with appropriate isotopically labeled reagents. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present invention may be replaced or substituted by deuterium. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Compounds of formula (I) can form salts which are also within the scope of the invention. It should be understood that, unless stated otherwise, references to compounds of the formula herein include references to their salts. The present invention relates to compounds as described herein and their pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers or tautomers, and The compound or a pharmaceutically acceptable salt, mirror image isomer, hydrate, solvate, prodrug, isomer or tautomer pharmaceutical composition thereof. In the present invention, the reference to formula (1b) includes a reference to formula (1b) -1 and is similar to formulas (Ic), (Id), and (Ig). In the present invention, reference to, for example, Formula 1b-1g includes reference to Formulas (1b) -1, (Ic) -1, (Id) -1, (1g) -1, and (Ih) -1.Compound The present invention provides a compound having a structure of formula (I),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. The present invention provides a compound having a structure of formula (Ia),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. The present invention provides a compound having a structure of formula (Ib),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. In certain embodiments, the present invention provides a compound having a structure of formula (Ib), which has a formula (Ib) -1:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of: among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . The present invention provides a compound having a structure of formula (Ic),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. In certain embodiments, the present invention provides a compound having a structure of formula (Ic) havingAnd its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of: and; among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 system; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . The present invention provides a compound having a structure of formula (Id),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. In certain embodiments, the present invention provides a compound having a structure of formula (Id), which has the formula (Id) -1:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Departments O, S,or; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 system; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , NH (C1 -C6 Alkyl) or N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . The present invention provides a compound having a structure of formula (Ie),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. The present invention provides a compound having a structure of the formula (If),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. The present invention provides a compound having a structure of formula (Ig),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. Compound of formula (If) in R1 The substituent does not contain a basic amine group. The sulfonylurea moiety in the compounds of formula (1g) allows the pka values of these compounds to be in the range of 5.2 to 6.2, thereby characterizing them as weak organic acids. Compounds of this structure can exhibit low volume distribution in vivo and can exhibit high plasma protein binding. In certain embodiments, the present invention provides a compound having a structure of formula (Ig) having the formula (Ig) -1:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Department of O or S; R1 Is selected from the group consisting of:and, R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently selected from H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 , -NS (O)2 R6 Substitution; or two of R on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NS (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Can form side oxygen; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, it may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O. The present invention provides a compound having a structure of formula (Ih),And its pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, isomers and tautomers, where X1 , R1 , R2 , R3 And R4 This is as described above. The compound of formula (Ih) contains a basic amine group. The incorporation of a basic amine group into a compound of formula (1h), which also carries an acid sulfonylurea moiety, is expected to exist as a zwitterion with a net zero charge. Zwitterionic compounds may have physicochemical properties that differ from weak organic acids. Significantly, there can be increased in vivo distribution of volume and reduced plasma protein binding. In certain embodiments, the present invention provides a compound having a structure of formula (Ih) having the formula (Ih) -1:And its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, of which: X1 Department of O or S; R1 Is selected from the group consisting of:and, R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently selected from H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl and N-containing heterocyclic groups; wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Replace; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, it may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O. In certain embodiments of formula I, at R1 system,orWhen at least one A2 Department N, NR5 , O, S, or S (O)2 . In certain embodiments of Formula Ia-Id, in R1 systemorWhen at least one A2 Department N, NR5a , O, S, or S (O)2 . In certain embodiments of the formulae described herein, X1 Department O. In some embodiments, X1 Department S. In some embodiments, X1 system. In some embodiments, X1 system. In certain embodiments of the formulae described herein, R2 system. In certain embodiments of formula I, R2 system. In certain embodiments of Formula Ia-Id, R2 system. In certain embodiments, R2 system. In certain embodiments, R2 system. In certain embodiments of the formulae described herein, R2 system. In certain embodiments of formula I, R5 H, D, halogen, CN, -OR6 Or C1 -C6 alkyl. In certain embodiments, R5 H, halogen or C1 -C6 alkyl. In certain embodiments, R5 Department H, halogen or methyl. In certain embodiments, R5 Department H, fluorine, chlorine or methyl. In certain embodiments, R5 Department H. In certain embodiments, R5 Department of halogen. In certain embodiments, R5 Department of fluorine. In certain embodiments, R5 Department of chlorine. In certain embodiments, R5 Department of methyl. In certain embodiments of Formula Ia-Id, R5b H, D, halogen, CN, -OR6 Or C1 -C6 alkyl. In certain embodiments, R5b H, halogen or C1 -C6 alkyl. In certain embodiments, R5b Department H, halogen or methyl. In certain embodiments, R5b Department H, fluorine, chlorine or methyl. In certain embodiments, R5b Department H. In certain embodiments, R5b Department of halogen. In certain embodiments, R5b Department of fluorine. In certain embodiments, R5b Department of fluorine. In certain embodiments, R5b Department of methyl. In certain embodiments of formula I, R2 system. In certain embodiments of Formula Ia-Id, R2 system. In certain embodiments, n is 0, 1 or 2. In certain embodiments of formula I, each R5 Independently H, halogen, OH, CN, -NO2 , -OR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C3 -C8 Cycloalkyl. In some embodiments, each R5 Independently selected from H, halogen, C1 -C6 Alkyl, C3 -C8 A group consisting of cycloalkyl and -CN. In certain embodiments of Formula Ia-Id, each R5b Independently H, halogen, OH, CN, -NO2 , -OR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C3 -C8 Cycloalkyl. In some embodiments, each R5b Independently selected from H, halogen, C1 -C6 Alkyl, C3 -C8 A group consisting of cycloalkyl and -CN. In certain embodiments of formula I, R2 system. In certain embodiments of Formula Ia-Id, R2 system. In certain embodiments of formula I, R2 system. In certain embodiments of Formula Ia-Id, R2 system. In certain embodiments of the formulae described herein, R2 From the group consisting of:and. In certain embodiments, wherein R2 From the group consisting of:and. In certain embodiments, R2 system. In certain embodiments of Formulae Ie-Ih, R2 systemWhere R5b2 , R5b3 , R5b4 , R5b5 And R5b6 At least one of them is C1 -C6 Alkyl or C3 -C8 Cycloalkyl, where these C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments, R5b2 , R5b3 , R5b4 , R5b5 And R5b6 At least one of them is C1 -C6 Alkyl or C3 -C8 Cycloalkyl, where these C1 -C6 Alkyl and C3 -C8 Cycloalkyl is optionally substituted with halogen. In certain embodiments of the formulae described herein, R1 Is optionally replaced by C1 -C6 alkyl. In certain embodiments, R1 Department C1 -C6 alkyl. In certain embodiments, R1 Department C1 -C3 alkyl. In certain embodiments, R1 Department of methyl. In certain embodiments, R1 Is optionally replaced by C1 -C6 Alkenyl. In certain embodiments, R1 Is optionally replaced by C1 -C6 Alkynyl. In certain embodiments, R1 Department- (CH2 )m -O- (CH2 )m -CH3 , Each m is independently an integer of 1 to 4. In certain embodiments of the formulae described herein, R1 Is selected from the group consisting of:In certain embodiments of the formulae described herein, R1 system. In certain embodiments of the formulae described herein, R1 system,orIn certain embodiments of the formulae described herein, R1 system,or. In certain embodiments of the formulae described herein, R1 system or. In certain embodiments of the formulae described herein, R1 system,or. In certain embodiments of the formulae described herein, R1 system or. In certain embodiments of the formulae described herein, R1 system. In certain embodiments, R1 system. In certain embodiments, R1 system. In certain embodiments of the formulae described herein,Department contains A2 A single bond in a ring, thereby forming a saturated ring. In some embodiments, 1 to 2Department contains A2 The double bond in the ring, thereby forming an unsaturated ring. In certain embodiments of formula I, A is CR5 . In certain embodiments of Formula Ia-Id, A is CR5a . In certain embodiments of the formulae described herein, A is N. In certain embodiments of formula I, A1 Department of NR5 . In certain embodiments of Formula Ia-Id, A1 Department of NR5a . In certain embodiments of the formulae described herein, A1 Department O. In certain embodiments of the formulae described herein, A1 Department S. In certain embodiments of the formulae described herein, A1 Department C (O). In certain embodiments of the formulae described herein, each A2 Independently CH2 Or O. In some embodiments, each A2 Department of CH2 . In certain embodiments of Formula I, an A is a CR5 And another A is N. In some embodiments, each A2 Independently C (R5 )2 , NR5 Or O. In certain embodiments of Formula Ia-Id, an A is a CR5a And another A is N. In some embodiments, each A2 Independently C (R5a )2 , NR5a Or O. In certain embodiments of formula I, R5 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In certain embodiments, C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted. In certain embodiments of Formula Ia, each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In certain embodiments, C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted. In certain embodiments of Formula Ia, each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In certain embodiments, C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted. In certain embodiments of formula I, two R5 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O. In certain embodiments, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted. In certain embodiments of Formula Ia-Id, two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O. In certain embodiments, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted. In certain embodiments, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OH, -NH2 , NH (C1 -C6 Alkyl) or N (C1 -C6 alkyl)2 To replace. In certain embodiments, two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments of the formulae described herein, two R's on the same carbon5 A pendant oxygen group can be formed. In certain embodiments of Formula Ia-Id, two R's on the same carbon5a A pendant oxygen group can be formed. In certain embodiments of Formula Ib-Id, each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OH, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments, R5a Department C1 -C6 Alkyl, optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , NH (C1 -C6 Alkyl) or N (C1 -C6 alkyl)2 To replace. In certain embodiments, R5a Is a heterocyclyl group, optionally through D, halogen, C1 -C6 Alkyl, -OH, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments of Formula Ib-Id, two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OH, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments, two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments of Formula Ib-Id, two R's on the same carbon5a A pendant oxygen group can be formed. In certain embodiments of Formula Ib-Id, each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments of formula I, each R5 Independently H, -NHR6 Or -NR6 R7 . In some embodiments, each A2 Independently C (R5 )2 Or O; and each R5 Independently H, -NHR6 Or -NR6 R7 . In certain embodiments of Formula Ia-Id, each R5a Independently H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups, wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In some embodiments, each A2 Independently C (R5a )2 Or O; and each R5a Independently H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups, wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments of the formulae described herein, R1 Is selected from the group consisting of:andWhere R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Substituted; and R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently selected from H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups, wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 To replace. In certain embodiments of the formulae described herein, R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P and O. In certain embodiments, C1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted. In certain embodiments of the formulae described herein, R6 And R7 Together with the atom to which it is attached, it may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O. In certain embodiments, heterocyclyl or heteroaryl is optionally substituted. In certain embodiments of Formula Ib-Id, R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments, R6 Department C1 -C6 Alkyl, optionally via D, halogen, C1 -C6 Alkyl, -OH, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments, R7 Department C1 -C6 Alkyl, optionally via D, halogen, C1 -C6 Alkyl, -OH, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. As described in Formula Ie above, R2 Can beWhere each Rb10 , Rb11 , Rb12 , Rb13 , Rb14 And Rb15 It is independently H, -OH or pendant. In certain embodiments, Rb10 , Rb11 , Rb12 , Rb13 , Rb14 And Rb15 One of them is -OH or pendant oxygen and the rest is H. In certain embodiments, Rb10 , Rb11 , Rb12 , Rb13 , Rb14 And Rb15 One of them is -OH and the others are H. In certain embodiments, Rb10 , Rb11 , Rb12 , Rb13 , Rb14 And Rb15 One of them is a pendant oxy group and the others are H. As described in formulae Ie-Ih above, X1 Department of O or S. In certain embodiments of Formulae Ie-Ig, X1 Department O. In some embodiments, X1 Department S. As described in formulae Ie-Ih above, R2 systemor. In certain embodiments of Formulae Ie-Ih, R2 system. As described in formulae Ie-Ih above, X2 Department of N or CR5b1 . In certain embodiments of Formulae Ie-Ih, X2 Department of CR5b1 . In some embodiments, X2 Department N. As described in formulae Ie-Ih above, R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In certain embodiments of Formulae Ie-Ih, R5b1 H, halogen or C1 -C6 alkyl. In certain embodiments, R5b1 Department H, halogen or methyl. In certain embodiments, R5b1 Department H, fluorine, chlorine or methyl. In certain embodiments, R5b1 Department H. In certain embodiments, R5b1 Department of halogen. In certain embodiments, R5b1 Department of fluorine. In certain embodiments, R5b1 Department of chlorine. In certain embodiments, R5b1 Department of methyl. In certain embodiments of Formulae Ie-Ih, R5b1 Is optionally replaced by C1 -C6 alkyl. In certain embodiments, R5b1 C is optionally substituted by halogen1 -C6 alkyl. In certain embodiments, R5b1 Department-OR6 . In certain embodiments, R5b1 Department -OH. In certain embodiments of Formulae Ie-Ih, R2 system. In certain embodiments, R2 system. In certain embodiments of Formulae Ie-Ih, R2 system. As described in formulae Ie-Ih above, each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 To replace. In certain embodiments of Formulae Ie-Ih, each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, CN, -NO2 , -OR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C3 -C8 Cycloalkyl. In some embodiments, each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently selected from H, D, halogen, C1 -C6 Alkyl, C3 -C8 A group consisting of cycloalkyl and -CN. In certain embodiments, R5b2 , R5b3 , R5b4 , R5b5 And R5b6 At least one of them is not hydrogen. In certain embodiments, R5b2 , R5b3 , R5b4 , R5b5 And R5b6 One of them -OR6 . In certain embodiments, R5b2 , R5b3 , R5b4 , R5b5 And R5b6 One of them is -OH. In certain embodiments of Formulae Ie-Ih, R2 system. In certain embodiments of Formulae Ie-Ih, R2 system. In certain embodiments of Formulae Ie-Ih, R2 From the group consisting of:and. In certain embodiments, wherein R2 From the group consisting of:,and. In certain embodiments, R2 system. In certain embodiments of Formulae Ie-Ih, two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 To replace. In some embodiments, two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl, where C3 -C8 Cycloalkyl and heterocyclyl are optionally halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 To replace. In certain embodiments of Formulae Ie-Ih, R2 system. In some embodiments, each R5b2 And R5b4 From the group consisting of: H, D, halogen, C1 -C6 Alkyl, C3 -C8 Cycloalkyl and -CN. In certain embodiments of Formulae Ie-Ih, R2 system. As described in formulae Ie-Ih above, R1 Is selected from the group consisting of: and,among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring. In certain embodiments of Formulae Ie-Ih,Represents a single key. In certain embodiments of Formulae Ie-Ih,Represents a double bond. In some embodiments,Department contains A2 A single bond in a ring, thereby forming a saturated ring. In certain embodiments of Formulae Ie-Ih, R1 systemor. In certain embodiments, R1 systemor. As described in formulae Ie-Ih above, each A is independently CR5a1 Or N; and every A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 . In certain embodiments of Formulae Ie-Ih, an A is CR5a1 And another A is N. In some embodiments, each A2 Independently C (R5a2 )2 , NR5a2 Or O. As described in formulae Ie-Ih above, each R5a1 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 To replace. In certain embodiments of Formulae Ie-Ih, each R5a1 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl or heterocyclyl, where these C1 -C6 Alkyl, C3 -C8 Cycloalkyl and heterocyclyl are optionally halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 To replace. As described in formulae Ie-Ih above, each R5a2 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2 Pendant oxygen groups can be formed; in certain embodiments of formulae Ie, If and Ig, each R5a2 Independently H, halogen, OH, -OR6 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl or heterocyclyl; where these C1 -C6 Alkyl, C3 -C8 Cycloalkyl and heterocyclyl are optionally halogen, C1 -C6 Alkyl, -OR6 , -NR6 C (O) OR6 Or -NR6 C (O) R6 To replace. In certain embodiments of formulae Ie, If and Ih, each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl or heterocyclyl; where these C1 -C6 Alkyl, C3 -C8 Cycloalkyl and heterocyclyl are optionally halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 To replace. In certain embodiments of formulae Ie, If and Ih, each R5a2 Independently H, -NHR6 Or C1 -C6 Alkyl; where the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 To replace. In some embodiments, each R5a2 Is independently H or a heterocyclic group containing N; wherein the heterocyclic group is optionally D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 To replace. In certain embodiments of formula Ie, If, each A2 Independently C (R5a2 )2 Or O; and each R5a2 Independently H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups; wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 To replace. In certain embodiments of formulae Ie-Ih, two R's on the same carbon5a2 A pendant oxygen group can be formed. In certain embodiments of Formula Ie-If, R1 Is selected from the group consisting of:andWhere R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently selected from H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two of R on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f A pendant oxygen group can be formed. In certain embodiments of Formulae Ie-Ig, R1 Is selected from the group consisting of:andWhere R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Selected from H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two of R on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f A pendant oxygen group can be formed. In certain embodiments of formulae Ie-If and Ih, R1 Is selected from the group consisting of:andWhere R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , - NR6 C (O) OR6 Or -NR6 C (O) R6 Substituted; and R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently selected from H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups; wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 To replace. In certain embodiments of the formulae described herein, R1 system. In some embodiments, an A-series CR5a1 And another A is N. In some embodiments, each A2 Independently C (R5a2 )2 , NR5a2 Or O. In certain embodiments, each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, two of R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 system, Which has the formulaWhere: A2ab Selected from CR5a2 , C (R5a2a ) (R5a2b ), N, NR5a2 , O, S, or S (O)2 ; A2cd Selected from CR5a2 , C (R5a2c ) (R5a2d ), N, NR5a2 , O, S, or S (O)2 ; A2ef Selected from CR5a2 , C (R5a2e ) (R5a2f ), N, NR5a2 , O, S, or S (O)2 ; A2gh Selected from CR5a2 , C (R5a2g ) (R5a2h ), N, NR5a2 , O, S, or S (O)2 ; Each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 ,-NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h A pendant oxygen group can be formed. In certain embodiments of the formulae described herein, R1 systemWhere where R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; R5a2c And R5a2d Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d A pendant oxygen group can be formed. In some embodiments, each R5a2c And R5a2d Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, each R5a2c And R5a2d Independently H, halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2c And R5a2d One of them is H and the other is independently halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 systemWhere R5a2a And R5a2b Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2a And R5a2b Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2a And R5a2b A pendant oxygen group can be formed. In some embodiments, each R5a2a And R5a2b Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, each R5a2a And R5a2b Independently H, halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2a And R5a2b One of them is H and the other is independently halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2a And R5a2b Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 systemWhere R5a2e And R5a2f Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2e And R5a2f A pendant oxygen group can be formed. In some embodiments, each R5a2e And R5a2f Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, each R5a2e And R5a2f Independently H, halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2e And R5a2f One of them is H and the other is independently halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 systemWhere R5a2c And R5a2d Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH( C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d A pendant oxygen group can be formed. In some embodiments, each R5a2c And R5a2d Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, each R5a2c And R5a2d Independently H, halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2c And R5a2d One of them is H and the other is independently halogen, OH, -OR6 , -NHR6 Or -NR6 R7 . In certain embodiments, R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 Is selected from the group consisting of: and,among themIt is connected to the rest of the compound. In certain embodiments of the formulae described herein, R1 Is selected from the group consisting of:and,among themIt is connected to the rest of the compound. In certain embodiments of the formulae described herein, R1 Is selected from the group consisting of:and,among themIt is connected to the rest of the compound. In certain embodiments of the formulae described herein, R1 system. In some embodiments, an A-series CR5a1 And another A is N. In some embodiments, each A2 Independently C (R5a2 )2 , NR5a2 Or O. In certain embodiments, each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, two of R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 system, Which has the formulaWhere A2ab Selected from CR5a2 , C (R5a2a ) (R5a2b ), N, NR5a2 , O, S, or S (O)2 ; A2cd Selected from CR5a2 , C (R5a2c ) (R5a2d ), N, NR5a2 , O, S, or S (O)2 ; A2ef Selected from CR5a2 , C (R5a2e ) (R5a2f ), N, NR5a2 , O, S, or S (O)2 ; A2gh Selected from CR5a2 , C (R5a2g ) (R5a2h ), N, NR5a2 , O, S, or S (O)2 ; A2ij Selected from CR5a2 , C (R5a2i ) (R5a2j ), N, NR5a2 , O, S, or S (O)2 ; Each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g , R5a2h , R5a2i And R5a2j Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g , R5a2h , R5a2i And R5a2j Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g , R5a2h , R5a2i And R5a2j A pendant oxygen group can be formed. In certain embodiments of the formulae described herein, R1 system. In certain embodiments of the formulae described herein, R1 system. In some embodiments, an A-series CR5a1 And another A is N. In some embodiments, each A2 Independently C (R5a2 )2 , NR5a2 Or O. In certain embodiments, each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, two of R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 system, Which has the formulaWhere A2ab Selected from C (R5a2a ) (R5a2b ), NR5a2 , O, S, or S (O)2 ; A2cd Selected from C (R5a2c ) (R5a2d ), NR5a2 , O, S, or S (O)2 ; A2ef Selected from C (R5a2e ) (R5a2f ), NR5a2 , O, S, or S (O)2 ; Each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f A pendant oxygen group can be formed. In certain embodiments of the formulae described herein, R1 system. In certain embodiments of the formulae described herein, R1 system. In some embodiments, an A-series CR5a1 And another A is N. In some embodiments, each A2 Independently C (R5a2 )2 , NR5a2 Or O. In certain embodiments, each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. In some embodiments, two of R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. In certain embodiments of the formulae described herein, R1 system, Which has the formulaWhere A2ab Selected from CR5a2 , C (R5a2a ) (R5a2b ), N, NR5a2 , O, S, or S (O)2 ; A2cd Selected from CR5a2 , C (R5a2c ) (R5a2d ), N, NR5a2 , O, S, or S (O)2 ; A2ef Selected from CR5a2 , C (R5a2e ) (R5a2f ), N, NR5a2 , O, S, or S (O)2 ; A2gh Selected from CR5a2 , C (R5a2g ) (R5a2h ), N, NR5a2 , O, S, or S (O)2 ; Each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution, or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution, or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h A pendant oxygen group can be formed. The invention provides compounds of formula Ie-If, wherein X1 Department O; R1 Is selected from the group consisting of:and; among themRepresents a single bond; each A2 Independently C (R5a2 )2 Or O; X2 Department of CR5b1 ; Each R5a1 Independently H or C1 -C6 Alkyl; where the C1 -C6 Alkyl via D, halogen, -OR6 , -NH2 , NH (C1 -C6 Alkyl), N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl or heterocyclyl; where these C1 -C6 Alkyl and heterocyclyl optionally via D, halogen, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 Or -S (O)2 -R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen or C1 -C6 Alkyl; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, -CN, -OR6 , C1 -C6 Alkyl or C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl or heteroaryl optionally via halogen or C1 -C6 Alkyl substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkynyl or aryl; where these C1 -C8 Alkyl, C2 -C8 Alkynyl and aryl are optionally D, halogen or C1 -C6 Alkyl substituted. In certain embodiments, the compound has the formula:. In certain embodiments, the compound has the formula:. In certain embodiments of formula (I), X1 Department O and R2 system. In certain embodiments of formula (I), X1 Department O and R1 system. In certain embodiments of formula (I), R1 systemAnd R2 system. In some embodiments, the invention provides compounds of formula (I),It has one, two or three of the following characteristics: a) X is O; b) R1 system; C) R2 systemD) X2 Department of CH or CF. In some embodiments, the invention provides compounds of formula (I),It has one, two or three of the following characteristics: a) X is O; b) R1 system; C) R2 systemD) X2 Department of CH. (I) In some embodiments, the present invention provides a compound of formula (I),It has one, two or three of the following characteristics: a) X is S; b) R1 system; C) R2 systemD) X2 Department of CH. In some embodiments, the invention provides compounds of formula (I),It has one, two or three of the following characteristics: a) X is O; b) R1 Is methyl; c) R2 systemD) X2 Department of CH. In some embodiments, the invention provides compounds of formula (I),It has one, two or three of the following characteristics: a) X is S; b) R1 Is methyl; c) R2 systemD) X2 Department of CH. In some embodiments, the invention provides compounds of formula (I),It has one, two or three of the following characteristics: a) X is O; b) R1 system; C) R2 systemD) X2 Department of CH. In some embodiments, the invention provides compounds of Formula Ie-If,It has one, two or three of the following characteristics: a) X is O; b) R1 system; C) R5a2c And R5a2d One of them is H and the other is independently halogen, OH, -OR6 , -NHR6 Or -NR6 R7 D) R2 systemE) X2 Department of CH or CF. In some embodiments, the invention provides compounds of formula (I),It has one, two or three of the following characteristics: a) X is O; b) R1 system; C) R2 system. In certain embodiments, the invention provides, N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H-pyridine Zolo [5,1-b] [1,3] oxazine-3-sulfonamide and its pharmaceutically acceptable salts. In certain embodiments, the invention provides, N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethane) methanesulfonamide and its pharmaceutically acceptable salt. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the invention providesAnd its pharmaceutically acceptable salts. In certain embodiments, the present invention provides a compound selected from the group consisting of and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, and tautomer thereof:In certain embodiments, the present invention provides a compound selected from the group consisting of and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, and tautomer thereof:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers: . In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers: . In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers: . In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts:. In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers: In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:. In certain embodiments, the present invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers:Unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present invention, only the hydrogen atom is replaced by deuterium or tritium, or13 C or14 C replaces a carbon atom, or15 N replaces the nitrogen atom, or17 O or18 Compounds in which O replaces an oxygen atom are within the scope of the present invention. The isotopically labeled compound can be used as a research or diagnostic tool.treatment method The disclosed compounds (eg, compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih) and their pharmaceutically acceptable salts have activity as pharmaceutical agents, as discussed herein. The present invention provides a method for treating or preventing a disease, disorder, or condition, which comprises the steps of administering an effective amount of a compound of the present invention and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, and Tautomers are individuals in need thereof to treat or prevent a disease, disorder, or condition. The present invention provides a compound of the present invention and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer and tautomer thereof, or a pharmaceutical composition of the present invention for use in treating or preventing an individual in need. Disease, illness, or condition. The present invention provides the use of the compound of the present invention and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, which are used to treat or prevent diseases and conditions in individuals in need. Or condition. The present invention provides the use of the compound of the present invention and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, which are used for the manufacture or treatment of diseases, disorders or conditions. Of the potion. In certain embodiments, the disease, disorder, or condition is a responder to inhibition of the activation of an inflammator. In a particular embodiment, the disease, disorder, or condition is a responder to the inhibition of activation of the NLRP3 inflammasome. According to this embodiment, the compound of the present invention or a pharmaceutically effective salt, solvate or prodrug thereof is a specific inhibitor of NLRP3. In another embodiment, the disease, disorder, or condition affects IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33, and Th17 cells. One or more of the responses are responsive. In certain embodiments, the disease, disorder, or condition is responsive to the modulation of one or more of IL-1β and IL-18. In one embodiment, the modulator inhibits one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, and IL-33. In one embodiment, the modulator inhibits one or more of IL-1β and IL-18. In one embodiment, Th17 cells are regulated by inhibiting the production and / or secretion of IL-17. In general embodiments, the disease, disorder or condition is a disease, disorder or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, kidney system, respiratory system, central nervous system, cancer or other malignant disease, and / Or caused by or related to pathogens. It should be understood that these general embodiments, which are defined in terms of broad categories of diseases, disorders, and conditions, are not mutually exclusive. In this regard, any particular disease, disorder, or condition may be classified according to one or more of the general embodiments described above. Non-limiting examples are type I diabetes, which are autoimmune diseases and diseases of the endocrine system. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the immune system. In a particular embodiment, the disease, disorder, or condition is an inflammatory disease, disorder, or condition, or an autoimmune disease, disorder, or condition. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the liver. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the lungs. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the skin. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system. In one embodiment, the disease, disorder, or condition is cancer, tumor, or other malignant disease. As used herein, cancer tumors and malignant diseases refer to diseases, disorders, or conditions, or cells or tissues associated with such diseases, disorders, or conditions, which are characterized by abnormal or abnormal cell proliferation, Differentiation and / or migration and often accompanied by abnormal or abnormal molecular phenotypes and / or abnormalities including one or more genetic mutations or other genetic changes associated with tumor formation, manifestation of tumor markers, expression of tumor suppressor genes or loss of activity Abnormal cell surface marker manifestations. In general embodiments, cancer, tumors, and malignant diseases may include, but are not limited to, sarcoma, lymphoma, leukemia, solid tumor, blastoma, glioma, carcinoma, melanoma, and metastatic cancer. A more extensive list of cancer tumors and malignancies can be found on the National Cancer Institutes website http://www.cancer.gov/cancertopics/types/alphalist, the entirety of which is incorporated herein by reference. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the renal system. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the gastrointestinal tract. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system. In another embodiment, the disease, disorder or condition is a disease, disorder or condition of the endocrine system. In one embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS). In one embodiment, the disease, disorder, or condition is caused by or associated with a pathogen. The pathogen can be, but is not limited to, a virus, bacteria, protozoa, parasite or fungus or any other organism capable of infecting mammals. Non-limiting examples of viruses include influenza virus, cytomegalovirus, Epstein Barr Virus, human immunodeficiency virus (HIV), alpha virus (e.g. Chikungunya, and Roche (Ross River virus), flavivirus (such as Dengue virus, Zika virus) and papilloma virus, but it is not limited to this. Non-limiting examples of pathogenic bacteria include Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Corynebacterium diphtheria diptheriae), Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Influenza influenza Hemophilus influenzae, Pasteureiia multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma human Type (Mycoplasma hominis), Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae Klebsiella pneumoniae), Pseudomonas (aeruginosa), Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhoid (Salmonella typhimurium) typhi), Borrelia burgdorferi, and Yersinia pestis, but are not limited thereto. Non-limiting examples of protozoa include Plasmodium, Babesia, Giardia, Entamoeba, Leishmania And trypanosomes, but not limited to this. Non-limiting examples of parasites include, but are not limited to, worms, including schistosomiasis, roundworms, roundworms, and trematodes. Non-limiting examples of fungi include, but are not limited to, Candida and Aspergillus. In a particular embodiment, the disease, disorder, or condition is selected from the group consisting of: constitutive inflammation, including cryptopyrin-associated cycle syndrome (CAPS): Muckle-Wells syndrome (MWS), familial Cold-induced autoinflammation syndrome (FCAS) and neonatal onset multi-system inflammatory disease (NOMID); including auto-inflammatory diseases: familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS) , Mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (H IDS), interleukin 1 receptor antagonist deficiency (DIRA), Majeed syndrome, purulent Arthritis, gangrenous pyoderma and acne (PAPA), single dual gene deficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency and immune disorders (PLAID), PLCG2-related Autoinflammation, antibody deficiency and immune disorders (APLAID), iron granulocyte anemia with B-cell immune deficiency, periodic fever, stunted development (SIFD); Sweet s syndrome, chronic nonbacterial Osteomyelitis (CNO), slow Recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, impetigo, bone hypertrophy, osteoinflammatory syndrome (SAPHO); autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid Arthritis, Behcet's disease, Sjogren's syndrome and Schnitzler syndrome; respiratory diseases, including idiopathic pulmonary fibrosis (IPF), chronic Obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestos lung, silicosis, and cystic fibrosis; diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria and brain damage from pneumococcal meningitis; metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout; eye diseases, including eyes Epitheliality, age-related macular degeneration (AMD), corneal infection, uveitis, and dry eye; kidney disease, including chronic kidney disease, oxalate nephropathy, and diabetic nephropathy; liver disease, including non- Severe steatohepatitis and alcoholic liver disease; inflammatory reactions of the skin, including contact allergies and sunburn; inflammatory reactions of the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset stear's disease (Still's disease), relapsing polychondritis; viral infections, including alpha virus (Trachovirus virus, Roche virus) and flavivirus (dengue virus and Zika virus), influenza, HIV; pyogenic sweat glanditis Skin diseases caused by (HS) and other cysts; cancers including lung cancer metastasis, pancreatic cancer, gastric cancer, spinal dysplasia syndrome, leukemia; polymyositis; stroke; myocardial infarction; graft versus host disease; hypertension; colon Inflammation; helminth infection; bacterial infection; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis, including Dressler's syndrome, ischemic reperfusion injury, and Any disease in NLRP3's germline cell line or somatic non-silent mutant individuals. In one of these non-limiting examples, the disease, disorder, or condition being treated is NASH. Activation of the NLRP3 inflammasome is essential for inflammatory recruitment in NASH, and inhibition of NLRP3 can both prevent and reverse liver fibrosis. By interrupting the function of NLRP3 inflammasomes in liver tissue, the compounds of the present invention can cause histological reduction of liver inflammation, reduced recruitment of macrophages and neutrophils, and inhibition of NF-κΒ activation. Inhibition of NLRP3 can reduce liver expression of pro-IL-1β and normalized liver and circulating IL-1β, IL-6 and MCP-1 levels, thereby assisting the treatment of diseases. In yet another of these non-limiting examples, the disease, disorder, or condition being treated is severe steroid-resistant (SSR) asthma. Respiratory tract infections induce the NLRP3 inflammasome / Caspase-1 / IL-1β signaling axis in the lungs, which promotes SSR asthma. The NLRP3 inflammasome recruits and activates caspase-1 to induce an IL-1β response. Therefore, the IL-β response induced by the NLRP3 inflammasome is important in controlling infection, however, excessive activation causes abnormal inflammation and is related to the pathogenesis of SSR asthma and COPD. The administration of a compound of the invention that targets a specific disease process is therapeutically more attractive than the use of steroids or IL-1β to non-specifically inhibit the inflammatory response. Therefore, using the compounds of the present invention to target the NLRP3 inflammasome / cystease-1 / IL-1β signaling axis can be used to treat SSR asthma and other steroid-resistant inflammation conditions. In yet another of these non-limiting examples, the disease, disorder, or condition being treated is Parkinson's disease. Parkinson's disease is the most common neurodegenerative dyskinesia and is characterized by the selective loss of dopamine neurons, with misfolded a-synuclein (Syn) accumulation into the Lewy body. Chronic microglial inflammation is evident early in the disease and has been proposed to drive the condition. An important role for microglial NLRP3 is assumed in the progression of Parkinson's disease. The NLRP3 inflammation system is activated by fibrillar Syn via a Syk kinase-dependent mechanism, and it also appears in the early stages of dopamine degeneration in the absence of Syn conditions and drives neuronal loss. The compounds of the present invention can block NLRP3 inflammasome activation by fibrillar Syn or mitochondrial dysfunction and thereby confer effective neuroprotection to the nigrostriatal dopamine system and assist in the treatment of Parkinson's disease. In certain embodiments, the method treats or prevents a disease or disorder, including but not limited to bacterial infection, viral infection, fungal infection, inflammatory bowel disease, coeliac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity , Rheumatoid arthritis, liver disease, liver fibrosis, liver steatosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In certain embodiments, the disease, disorder, or condition is selected from the group consisting of: NASH (non-alcoholic steatohepatitis); CAPS (cryptothermal protein-related periodic syndrome); IPF (idiopathic pulmonary fibrosis) ; MI (R / I) (myocardial infarction and reperfusion injury); gout; I / O (immuno-oncology); asthma; IBD (inflammatory bowel disease); renal fibrosis; adult-onset stear's disease Systemic juvenile idiopathic arthritis; tumor necrosis factor receptor-associated periodic syndrome (TRAPS); colchicine-resistant familial Mediterranean fever (FMF); hyper-IgD syndrome (HIDS) / mevalonate kinase Deficiency (MKD); traumatic brain injury; Parkinson's disease; moderate to severe inflammatory acne; acute non-previous non-infectious uveitis (NIU); AD (Alzheimer's disease); COPD (Chronic obstructive pulmonary disease); sepsis; MS (multiple sclerosis); Bessette's disease; RA (rheumatoid arthritis); erosive osteoarthritis; T1D (type 1 diabetes); T2D (type 2 diabetes) Obesity osteoporosis cystic fibrosis alcoholic liver disease aging aging HCC (hepatocellular carcinoma) depression Endometriosis; gangrenous pyoderma ("PG"), rare ulcerative skin disease; lupus nephritis; epilepsy; ischemic stroke; deafness; sickle cell disease; SLE (systemic lupus erythematosus); And spinal cord injury. For the therapeutic uses mentioned above, of course, the dosage administered will vary depending on the compound used, the mode of administration, the desired treatment and adaptation to the condition. For example, the daily dose (if inhaled) of a compound of the invention may be in the range of about 0.05 micrograms / kg body weight (μg / kg) to about 100 micrograms / kg body weight (μg / kg). Alternatively, if the compound is administered orally, the daily dose of the compound of the present invention may be in the range of about 0.01 micrograms / kg body weight (μg / kg) to about 100 milligrams / kg body weight (mg / kg).Pharmaceutical composition The disclosed compounds (e.g., compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih) and their pharmaceutically acceptable salts can be used by themselves, but will generally be administered in the form of a pharmaceutical composition, Compounds / salts disclosed therein (e.g., compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih and their salts) (active ingredients) and pharmaceutically acceptable adjuvants, diluents or carriers剂 association. Custom procedures for selecting and preparing suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals-The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988, the entirety of which is incorporated herein by reference. Depending on the mode of administration, the pharmaceutical composition will contain from about 0.05% w to about 99% w (weight percent), more specifically from about 0.05% w to about 80% w, and still more specifically about 0.10% w Active ingredients to about 70% w and even more specifically about 0.10% w to about 50% w, all weight percentages are based on the total composition. The present invention also provides a pharmaceutical composition comprising a disclosed compound as defined above (eg, compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih) or a pharmaceutically acceptable salt thereof And pharmaceutically acceptable adjuvants, diluents or carriers. The present invention further provides a method for preparing a pharmaceutical composition of the present invention, comprising mixing a compound disclosed as defined above (for example, compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih) or A pharmaceutically acceptable salt and a pharmaceutically acceptable adjuvant, diluent or carrier. Pharmaceutical compositions can be, for example, creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols, and dry powder formulations (e.g., called Turbuhaler® Formulation in an inhaler device) for topical administration (e.g., to the skin or lungs and / or airways); or (e.g., by oral administration to the whole body in the form of a tablet, capsule, syrup, powder or granule Sexual administration; or by parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular or infusion) in the form of sterile solutions, suspensions or emulsions for injection; or rectal administration in the form of suppositories. Dry powder formulations of compounds of the present invention (including pharmaceutically acceptable salts) and pressurized HFA aerosols can be administered by oral or nasal inhalation. For inhalation, the compounds are desirably subdivided. The finely divided compound preferably has a mass median diameter of less than 10 micrometers (μm) and can be aided by a dispersant such as C8 -C20 Fatty acids or their salts (such as oleic acid), bile salts, phospholipids, alkyl sugars, perfluorinated or polyethoxylated surfactants or other pharmaceutically acceptable dispersants) are suspended in the propellant mixture. The compounds of the invention can also be administered by means of a dry powder inhaler. The inhaler may be a single-dose or multiple-dose inhaler, and may be a breath-actuated dry powder inhaler. One possibility is to mix the finely divided compounds of the invention with a carrier substance such as a monosaccharide, disaccharide or polysaccharide, a sugar alcohol or another polyol. Suitable carriers are sugars, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively, the finely divided compound may be coated with another substance. The powder mixture can also be dispensed into hard gelatin capsules, each capsule containing the desired dose of active compound. Another possibility is to process the finely divided powder into a sphere, which breaks down during the inhalation procedure. This spheroidized powder can be filled into a multi-dose inhaler (e.g. called Turbuhaler® Or, where the dosage unit measures the desired dose which is subsequently inhaled by the patient) in a drug reservoir. With this system, active ingredients are delivered to a patient with or without a carrier substance. Another possibility is to process the compound into an amorphous dispersion in a polymer matrix such as hydroxypropyl methyl cellulose (HPMC) or hydroxypropyl methyl cellulose acetate succinate (HPMCAS). As the name suggests, spray-dried dispersions (SDDs) are obtained by dissolving drugs and polymers in organic solvents, atomizing the resulting solution into droplets, and evaporating to dry solid particles. SDD is generally suitable for use in a variety of final oral dosage forms, including capsules and lozenges. For oral administration, the compounds of the invention may be mixed with the following adjuvants or carriers: for example, lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch, or amylopectin; cellulose derivatives A binder such as gelatin or polyvinylpyrrolidone; and / or a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like; and subsequently compressed into a lozenge. If a coated tablet is required, the core prepared as described above may be coated with a concentrated sugar solution that may contain, for example, acacia, gelatin, talc, and titanium dioxide. Alternatively, the lozenges may be coated with a suitable polymer dissolved in an easily volatile organic solvent. For the preparation of soft gelatin capsules, the compounds of the invention can be mixed with, for example, vegetable oils or polyethylene glycols. Hard gelatin capsules may contain granules of a compound using the above-mentioned excipients for tablets. Liquid or semi-solid formulations of the compounds of the invention can also be filled into hard gelatin capsules. Liquid preparations for oral application may be in the form of a syrup or suspension (e.g. a solution containing a compound of the invention, the remainder being a sugar and a mixture of ethanol, water, glycerol and propylene glycol). Optionally, these liquid preparations may contain colorants, flavoring agents, saccharin, and / or carboxymethyl cellulose as thickeners or other excipients known to those skilled in the art.Combination therapy The compounds of the present invention (that is, the compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih and their pharmaceutically acceptable salts) can also be administered in combination with other compounds for treating the above-mentioned conditions. Therefore, the present invention is further related to combination therapy, wherein the compound of the present invention or a pharmaceutical composition or formulation comprising the compound of the present invention is administered simultaneously or sequentially or as a combined preparation with another therapeutic agent or agent for treating List one or more of the conditions.Method of synthesizing compounds The compounds of the invention can be prepared by a variety of methods, including standard chemical methods. A suitable synthetic route is shown in the scheme provided below. Compounds of the invention (e.g., compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih) or pharmaceutically acceptable salts, mirror isomers, hydrates, solvates, prodrugs, Isomers or tautomers can be prepared by the following synthetic schemes by methods known in organic synthesis techniques as described in the section. In the following schemes, it should be fully understood that, if necessary, protective groups of sensitive or reactive groups are employed in accordance with general principles or chemical methods. Protective groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999, the entire contents of which are incorporated herein by reference). These groups are removed at a convenient stage of compound synthesis using methods apparent to those skilled in the art. The selection process and reaction conditions and their order of execution should be consistent with the preparation of the disclosed compounds (eg, compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih). Those skilled in the art will recognize the presence of stereocenters in compounds of formula (I). Therefore, the present invention includes two possible stereoisomers (unless specified in the synthetic method), and includes not only racemic compounds but also individual mirror isomers and / or non-image isomers. When it is desired that the compound is in the form of a single mirror isomer or non-mirro isomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. The final product, intermediate, or starting material can be resolved by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds", E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994), the entire contents of which are incorporated herein by reference. The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic methods.Preparation of compounds The compounds of the present invention can be prepared in a variety of ways that are familiar to those skilled in the art of organic synthesis. For example, the following methods and synthetic methods known in the field of synthetic organic chemistry or variations of these methods known to those skilled in the art can be used to synthesize the compounds of the present invention. Exemplary methods include, but are not limited to, those methods described below. The compounds of the invention can be synthesized by following the steps outlined in Scheme 1. The starting materials are commercially available or prepared by procedures known in the reported literature or as exemplified. Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih can be prepared according to the general procedures outlined in Scheme 1. In Method A, the disclosed compounds (eg, compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih) are prone to be derived from sulfoisocyanate or sulfoisothiocyanate (Compound A-1) is obtained by reaction with an amine (compound A-2). In certain embodiments, Compound A-2 is treated with a base in a suitable solvent. Subsequently, compound A-1 is added to compound A-2. The reaction is performed in a suitable solvent (for example, tetrahydrofuran or dichloromethane) at room temperature to reflux temperature. Continuing to refer to Scheme 1, in Method B, it is easy to obtain a compound of formula (I) from the reaction of isocyanate or isothiocyanate (compound B-1) and sulfonamide (compound B-2). In certain embodiments, Compound B-2 is treated with a base in a suitable solvent. Subsequently, compound B-1 is added to compound B-2. The reaction is performed in a suitable solvent (for example, tetrahydrofuran or dichloromethane) at room temperature to reflux temperature.Program 1 Example embodiment Example I-1. A compound of formula I,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , and; among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5 Or N; A1 Department of NR5 , O, S or C (O); each A2 Independently CR5 , C (R5 )2 , N, NR5 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5 ; R3 And R4 Department H; each R5 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; or two R5 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; or two in R on the same carbon5 Can form side oxygen; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5 , O, S, or S (O)2 . Example I-2. The compound of Example I-1, wherein X1 Department O. Example I-3. The compound of Example I-1, wherein X1 Department S. Example I-4. The compound of any one of Examples I-1 to I-3, wherein R2 system. Example I-5. The compound of any one of Examples I-1 to I-3, wherein R2 system. Example I-6. The compound of any one of Examples I-1 to I-5, wherein theseDepartment contains A2 A single bond in a ring, thereby forming a saturated ring. Example I-7. The compound of any one of Examples I-1 to I-5, wherein R1 system. Example I-8. The compound of Example I-7, wherein each A2 Independently CH2 Or O. Example I-9. The compound of any one of Examples I-1 to I-5, wherein R1 system. Example I-10. The compound of any one of Examples I-1 to I-5, wherein R1 Department of methyl. Example I-11. The compound of any one of Examples I-1 to I-9, wherein the compound has the formula:. Example I-12. The compound of Example I-1, which is, N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H-pyridine Zolo [5,1-b] [1,3] oxazine-3-sulfonamide. Example I-13. The compound of Example I-1, which is, N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamidino) methanesulfonamide. Example I-14. The compound of Example I-1 selected from the group consisting of: . Example I-15. A pharmaceutical composition comprising the compound of any one of Examples I-1 to I-14 and a pharmaceutically acceptable carrier. Embodiment I-16. A method for treating or preventing a disease, disorder, or condition, comprising the steps of administering an effective amount of a compound as in any one of Embodiments I-1 to I-14 or a pharmaceutically acceptable compound thereof Accepted salts, prodrugs, solvates, hydrates, isomers or tautomers to treat or prevent the disease, disorder, or condition. Embodiments I-17. The method of Embodiments I-16, wherein the disease, disorder, or condition is responsive to the inhibition of an inflamed body. Embodiment I-18. The method of Embodiments I-16 or I-17, wherein the disease, disorder, or condition is a responder to the inhibition of activation of the NLRP3 inflammasome. Embodiment I-19. The method of Embodiments I-16 or I-17, wherein the disease, disorder, or condition affects IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37 , IL-22, IL-33, and Th17 cells respond to the regulation of one or more. Embodiment I-20. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system. Embodiment I-21. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition, or an autoimmune disease, disorder, or condition. Embodiment I-22. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a liver disease, disorder, or condition. Embodiment I-23. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the lung. Embodiment I-24. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the skin. Embodiment I-25. The method of any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system. Embodiment I-26. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is cancer, tumor, or other malignant disease. Embodiment I-27. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the renal system. Embodiment I-28. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the gastrointestinal tract. Embodiment I-29. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system. Embodiment I-30. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the endocrine system. Embodiment I-31. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS). Embodiment I-32. The method of any one of Embodiments I-16 to I-19, wherein the disease, disorder, or condition is selected from the group consisting of: constitutive inflammation, cryptothermia-related cycle syndrome (CAPS ), Mu-Werner's syndrome (MWS), familial cold-induced autoinflammation syndrome (FCAS), neonatal onset multi-system inflammatory disease (NOMID), auto-inflammatory disease, familial Mediterranean fever (FMF) ), TNF receptor-related periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Margid's syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA), single dual gene deficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency and Immune disorders (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune disorders (APLAID), iron granulocyte anemia with B-cell immune deficiency, periodic fever, developmental delay (SIFD), Schwert's syndrome, chronic Nonbacterial osteomyelitis (CNO), chronic recurrent multiple lesions Osteomyelitis (CRMO) and synovitis, acne, impetigo, osteoporosis, osteoinflammatory syndrome (SAPHO), autoimmune diseases (including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Bessette's disease, Hugh's syndrome, Schnitzler's syndrome), respiratory diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestos lung, Silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, metabolic disease , Type 2 diabetes, atherosclerosis, obesity, gout, pseudogout, eye disease, ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic kidney disease , Oxalate nephropathy, diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, skin inflammatory response, contact allergy, sunburn, joint inflammatory response, osteoarthritis, systemic adolescent idiopathic Sex Arthritis, adult-onset stear's disease, relapsing polychondritis, viral infection, alphavirus infection, ququs virus infection, Roche virus infection, flavivirus infection, dengue virus infection, zika virus infection, Influenza, HIV infection, purulent sweat glanditis (HS), dermatosis caused by cysts, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, spinal dysplasia syndrome, leukemia, polymyositis, stroke, myocardial infarction, transplantation Physical versus host disease, hypertension, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Dresler syndrome, ischemic reperfusion injury, and Any disease in an individual identified as having a germline cell line or somatic non-silent mutation in NLRP3. Embodiment I-33. The method of Embodiment I-15, wherein the disorder is selected from the group consisting of bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, Metabolic syndrome, obesity, rheumatoid arthritis, liver disease, liver steatosis, fatty liver disease, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Example I-34. The method of Example I-33, wherein the condition is non-alcoholic steatohepatitis (NASH). Example I-35. The method of any one of Examples I-16 to I-34, wherein the treatment or prevention of the disease, disorder, or condition is performed on a mammal. Example I-36. The method of Example I-35, wherein the mammal is a human individual. Example I-37. A method for modulating the activity of a biological target, comprising exposing the biological target to a compound of any one of Examples I-1 to I-14, or a pharmaceutically effective salt, solvent thereof Drug or prodrug step. Embodiment I-38. The method according to embodiment I-37, wherein the biological target can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α , IL-37, IL-22, IL-33 and Th17 cells. Example I-39. The use of a compound of any one of Examples I-1 to I-14 for the treatment of a disease, disorder, or condition that is responsive to the inhibition of an inflamed body. Example I-40. The compound of any one of Examples I-1 to I-14 for use in the manufacture of a medicament for the treatment of a disease, disorder, or condition that is responsive to the inhibition of an inflamed body. Example II-1. A compound of formula Ia,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; or two in R on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; or two R5b Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . Example II-2. A compound of formula Ib,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . Example II-3. A compound of formula Ic,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkenyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 ,among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 system; X2 Department of N or CR5b ; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . Example II-4. A compound of formula Id,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Departments O, S,or; R1 Is selected from the group consisting of: optionally substituted C1 -C6 Alkyl, optionally substituted C1 -C6 Alkynyl,-(CH2 )m -O- (CH2 )m -CH3 , among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a Or N; A1 Department of NR5a , O, S or C (O); each A2 Independently CR5a , C (R5a )2 , N, NR5a , O, S, or S (O)2 ; R2 system; R3 And R4 Department H; each R5a Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5a Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; where the C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R's on the same carbon5a Can form pendant oxygen groups; each R5b Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -S (O)2 N (R6 )2 -, -S (O)2 R6 , -C (O) R6 , -C (O) OR6 , -C (O) NR6 R7 , -NR6 S (O)2 R7 , -S (O) R6 , -S (O) NR6 R7 , -NR6 S (O) R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl and C2 -C6 Alkynyl via D, halogen, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl; where the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C6 Alkyl, C2 -C8 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally pass D, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 Together with the atom to which it is attached, may form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; each m is independently an integer of 1 to 4; and n is an integer from 0 to 5; conditions are inclusive of A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a , O, S, or S (O)2 . Example II-5. The compound of any one of Examples II-1 to II-4, wherein R1 Is selected from the group consisting of: Example II-6. The compound of any one of Examples II-1 to II-5, wherein X1 Department O. Example II-7. The compound of any one of Examples II-1 to II-5, wherein X1 Department S. Example II-8. The compound of any one of Examples II-1 to II-3 and II-5 to II-7, wherein R2 system. Example II-9. The compound of any one of Examples II-1 to II-3 and II-5 to II-7, wherein R2 system. Example II-10. The compound of any one of Examples II-1 to II-9, wherein theseContains A2 A single bond in a ring, thereby forming a saturated ring. Example II-11. The compound of any one of Examples II-1 to II-10, wherein R1 system. Example II-12. The compound of Example II-11, wherein each A2 Independently CH2 Or O. Example II-13. The compound of any one of Examples II-1 to II-10, wherein R1 system. Example II-14. The compound of any one of Examples I-1 to II-10, wherein R1 system. Example II-15. The compound of any one of Examples II-1 to II-10, wherein R1 system. Example II-16. The compound of any one of Examples II-1 to II-15, wherein R1 Department of methyl. Example II-17. The compound of any one of Examples II-1 to II-3 and II-5 to II-16, wherein the compound has the formula:. Example II-18. The compound of Example II-1, which is, N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H-pyridine Zolo [5,1-b] [1,3] oxazine-3-sulfonamide or a pharmaceutically acceptable salt thereof. Example II-19. The compound of Example II-1, which is, N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamidino) methanesulfonamide or its pharmaceutically acceptable salt. Example II-20. The compound of Example II-1, which is, Or a pharmaceutically acceptable salt thereof. Example II-21. The compound of claim II-1, which is:, Or a pharmaceutically acceptable salt thereof. Example II-22. The compound of Example II-1, which is selected from the group consisting of:Example II-23. The compound of Example II-1, which is selected from the group consisting of: . Example II-24. The compound of any one of Examples II-1 to II-4, which is selected from the group consisting of: Example II-25. A pharmaceutical composition comprising the compound of any one of Examples II-1 to II-24 and a pharmaceutically acceptable carrier. Embodiment II-26. A method for treating or preventing a disease, disorder or condition, comprising the steps of administering an effective amount of a compound according to any one of Embodiments II-1 to II-24 or a pharmaceutically acceptable compound thereof. Accepted salts, prodrugs, solvates, hydrates, isomers or tautomers to treat or prevent the disease, disorder, or condition. Embodiments II-27. The method of Embodiments II-25, wherein the disease, disorder, or condition is responsive to inhibition of an inflamed body. Embodiments II-28. The method of Embodiments II-26 or II-27, wherein the disease, disorder, or condition is a responder to the inhibition of activation of the NLRP3 inflammasome. Embodiment II-29. The method of Embodiment II-26 or II-27, wherein the disease, disorder or condition is against IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37 , IL-22, IL-33, and Th17 cells respond to the regulation of one or more. Embodiment II-30. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system. Embodiment II-31. The method of any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition, or an autoimmune disease, disorder, or condition. Embodiment II-32. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a liver disease, disorder, or condition. Embodiment II-33. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the lung. Embodiment II-34. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a skin disease, disorder, or condition. Embodiment II-35. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system. Embodiment II-36. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is cancer, tumor, or other malignant disease. Embodiment II-37. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the renal system. Embodiment II-38. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the gastrointestinal tract. Embodiment II-39. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system. Embodiment II-40. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the endocrine system. Embodiment II-41. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS). Embodiment II-42. The method of any one of Embodiments II-26 to II-29, wherein the disease, disorder, or condition is selected from the group consisting of: constitutive inflammation, cryptopyrin-related cycle syndrome (CAPS ), Mu-Werner's syndrome (MWS), familial cold-induced autoinflammation syndrome (FCAS), neonatal onset multi-system inflammatory disease (NOMID), auto-inflammatory disease, familial Mediterranean fever (FMF) ), TNF receptor-related periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Margid's syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA), single dual gene deficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency and Immune disorders (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune disorders (APLAID), iron granulocyte anemia with B-cell immune deficiency, periodic fever, developmental delay (SIFD), Schwert's syndrome, chronic Nonbacterial osteomyelitis (CNO), chronic recurrent disease Focal osteomyelitis (CRMO) and synovitis, acne, impetigo, bone hypertrophy, osteoinflammatory syndrome (SAPHO), autoimmune diseases (including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis , Bessette's disease, Hughlen's syndrome, Schnitzler's syndrome), respiratory diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestos lung , Silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, metabolism Disease, type 2 diabetes, atherosclerosis, obesity, gout, pseudogout, eye disease, ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic Nephropathy, oxalate nephropathy, diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, skin inflammation, contact allergies, sunburn, joint inflammation, osteoarthritis, systemic adolescent characteristics hair Osteoarthritis, adult-onset stear's disease, relapsing polychondritis, viral infection, alphavirus infection, ququs virus infection, Roche virus infection, flavivirus infection, dengue virus infection, zika virus infection , Influenza, HIV infection, pyogenic sweat glanditis (HS), dermatosis caused by cysts, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, spinal dysplasia syndrome, leukemia, polymyositis, stroke, myocardial infarction, Graft-versus-host disease, hypertension, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Dresler syndrome, ischemic reperfusion injury, And any disease in an individual who has been determined to have a non-silent mutation in a germline cell line or somatic cell of NLRP3. Embodiment II-43. The method of Embodiment II-26, wherein the disorder is selected from the group consisting of bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, Metabolic syndrome, obesity, rheumatoid arthritis, liver disease, liver steatosis, fatty liver disease, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Embodiments II-44. The method of Embodiments II-43, wherein the disorder is non-alcoholic steatohepatitis (NASH). Embodiment II-45. The method of any one of Embodiments II-26 to II-44, wherein the treatment or prevention of the disease, disorder, or condition is performed on a mammal. Embodiments II-46. The method of Embodiments II-45, wherein the mammal is a human individual. Example II-47. A method for modulating the activity of a biological target, which comprises exposing the biological target to a compound of any one of Examples II-1 to II-24 or a pharmaceutically effective salt or solvent thereof Drug or prodrug step. Embodiment II-48. The method according to embodiment II-47, wherein the biological target can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α , IL-37, IL-22, IL-33 and Th17 cells. Example II-49. Use of a compound according to any one of Examples II-1 to II-24 for the treatment of a disease, disorder, or condition that is responsive to the inhibition of an inflamed body. Example II-50. The compound of any one of Examples II-1 to II-24 for use in the manufacture of a medicament for the treatment of a disease, disorder, or condition that is responsive to the inhibition of an inflamed body. Example III-1. A compound of Formula If,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; each R5a1 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . Example III-2. The compound of Example III-1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Department O; R1 Is selected from the group consisting of: and; among themRepresents a single bond; each A2 Independently C (R5a2 )2 Or O; X2 Department of CR5b1 ; Each R5a1 Independently H or C1 -C6 Alkyl; where the C1 -C6 Alkyl via D, halogen, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl or heterocyclyl; where these C1 -C6 Alkyl and heterocyclyl optionally via D, halogen, -OR6 , -NH2 , NH (C1 -C6 Alkyl), N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 Or -S (O)2 -R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen or C1 -C6 Alkyl; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, -CN, -OR6 , C1 -C6 Alkyl or C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or two R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl or heteroaryl optionally via halogen or C1 -C6 Alkyl substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkynyl or aryl; where these C1 -C8 Alkyl, C2 -C8 Alkynyl and aryl are optionally D, halogen or C1 -C6 Alkyl substituted. Example III-3. A compound of formula Ig,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; each R5a1 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . Example III-4. A compound of formula Ih,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; R3 And R4 Department H; each R5a1 Independently H, D, halogen, -OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1-C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or at least one of R5a2 Department-NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups, wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Replace; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . Example III-5. A compound of formula Ie,Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X1 Department of O or S; R1 Is selected from the group consisting of:among themRepresents a single or double bond, and the condition consists of one or more A2 The ring is a non-aromatic ring; each A is independently CR5a1 Or N; each A2 Independently CR5a2 , C (R5a2 )2 , N, NR5a2 , O, S, or S (O)2 ; R2 systemor; X2 Department of N or CR5b1 ; Each Rb10 , Rb11 , Rb12 , Rb13 , Rb14 And Rb15 Independently H, -OH or pendant oxygen; R3 And R4 Department H; each R5a1 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; each R5a2 Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2 Can form side oxygen; R5b1 H, D, halogen, -CN, -OR6 Or C1 -C6 Alkyl, C3 -C8 Cycloalkyl, -C (O) NR6 , -C (O) OR6 ; Of which C1 -C6 Alkyl and C3 -C8 Cycloalkyl via D, halogen, -CN, -OR as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, -CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl or C2 -C6 Alkynyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C3 -C8 Cycloalkyl and C2 -C6 Alkynyl via D, halogen, -CN, -OR, as appropriate6 , -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Replace; or two adjacent R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Forms C with the atom to which it is attached3 -C8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C3 -C8 Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl) or- N (C1 -C6 alkyl)2 Substituted; and R6 And R7 Independently H, D, C at each occurrence1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where the C1 -C8 Alkyl, C2 -C8 Alkenyl, C2 -C8 Alkynyl, C3 -C8 Cycloalkyl, C4 -C8 Cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C1 -C6 Alkyl, -OH, -O-C1 -C6 Alkyl, -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substitution; or R6 And R7 With its attached atoms, it can form a heterocyclic or heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; provided that it contains A and / or A1 When the ring is imidazole, then at least one A2 Department N, NR5a2 , O, S, or S (O)2 . Example III-6. The compound of any one of Examples III-1 and III-3 to III-5 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer thereof, or Tautomers, where X1 Department O. Example III-7. The compound of any one of Examples III-1 to III-6 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Example III-8. The compound of Example III-7 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein X2 Department of CR5b1 . Example III-9. The compound of Example III-8 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R5b1 H, halogen or C1 -C6 alkyl. Example III-10. The compound of Example III-8 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R5b1 Department H, fluorine, chlorine or methyl. Example III-11. The compound of any one of Examples III-1 to III-10 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Example III-12. The compound of any one of Examples III-1 to III-10 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Example III-13. The compound of any one of Examples III-1 to III-6 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Examples III-14. The compound of Example III-13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently H, D, halogen, OH, CN, -NO2 , -OR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl or C3 -C8 Cycloalkyl. Example III-15. The compound of any one of Examples III-1 to III-13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Example III-16. The compound of Example III-15 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R5b2 , R5b3 , R5b4 , R5b5 And R5b6 Independently selected from H, D, halogen, C1 -C6 Alkyl, C3 -C8 A group consisting of cycloalkyl and -CN. Example III-17. The compound of any one of Examples III-1 to III-16 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 From the group consisting of: and. Example III-18. The compound of any one of Examples III-1 to III-17 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 From the group consisting of:and. Example III-19. The compound of any one of Examples III-1 to III-18 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Example III-20. The compound of any one of Examples III-1 to III-13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Examples III-21. The compound of Example III-20 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R5b2 And R5b4 From the group consisting of: H, D, halogen, C1 -C6 Alkyl, C3 -C8 Cycloalkyl and -CN. Example III-22. The compound of any one of Examples III-20 and III-21 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R2 system. Example III-23. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 systemor. Example III-24. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 systemor. Example III-25. The compound of any one of Examples III-1 to III-24 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof , One of the A series CR5a1 And another A is N. Example III-26. The compound of any one of Examples III-1 to III-25 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where each A2 Independently C (R5a2 )2 , NR5a2 Or O. Example III-27. The compound of Example III-26, wherein each R5a2 Independently H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups, wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 To replace. Example III-28. The compound of Example III-27, wherein R1 Is selected from the group consisting of:andWhere R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Substituted; and R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently selected from H, -NHR6 , -NR6 R7 , C1 -C6 Alkyl or N-containing heterocyclic groups, wherein the C1 -C6 Alkyl via -NH2 , -NH (C1 -C6 Alkyl) or -N (C1 -C6 alkyl)2 Substituted, and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 , -NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 To replace. Example III-29. The compound of any one of Examples III-1 to III-23 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system. Examples III-30. The compound of Example III-29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein one of A is CR5a1 And another A is N. Example III-31. The compound of any one of Examples III-29 to III-30 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where each A2 Independently C (R5a2 )2 , NR5a2 Or O. Example III-32. The compound of any one of Examples III-29 to III-30 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where each R5a2 Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. Example III-33. The compound of any one of Examples III-20 to III-32 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Of which two R5a2 Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. Example III-34. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system, Which has the formulaWhere A2ab Selected from CR5a2 , C (R5a2a ) (R5a2b ), N, NR5a2 , O, S, or S (O)2 ; A2cd Selected from CR5a2 , C (R5a2c ) (R5a2d ), N, NR5a2 , O, S, or S (O)2 ; A2ef Selected from CR5a2 , C (R5a2e ) (R5a2f ), N, NR5a2 , O, S, or S (O)2 ; And A2gh Selected from CR5a2 , C (R5a2g ) (R5a2h ), N, NR5a2 , O, S, or S (O)2 ; Each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h A pendant oxygen group can be formed. Example III-35. The compound of Example III-34 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 systemWhere where R5a1a H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -NR6 C (O) R6 , -NR6 C (O) OR6 , -NR6 C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 Or -NR6 C (O) R6 Replace; R5a2c And R5a2d Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH( C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d A pendant oxygen group can be formed. Example III-36. The compound of Example III-35 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R5a2c And R5a2d Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. Example III-37. The compound of any one of Examples III-35 to III-36 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. Example III-38. The compound of Example III-34 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 systemWhere R5a2a And R5a2b Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2a And R5a2b Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2a And R5a2b A pendant oxygen group can be formed. Examples III-39. The compound of Example III-38 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R5a2a And R5a2b Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. Example III-40. The compound of any one of Examples III-38 to III-39 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R5a2a And R5a2b Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. Example III-41. The compound of Example III-33 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 systemWhere R5a2e And R5a2f Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2e And R5a2f A pendant oxygen group can be formed. Example III-42. The compound of Example III-41 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R5a2e And R5a2f Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. Example III-43. The compound of any one of Examples III-41 to III-42 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. Examples III-44. The compound of Example III-34 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 systemWhere R5a2c And R5a2d Each independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH( C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or R5a2c And R5a2d A pendant oxygen group can be formed. Examples III-45. The compound of Example III-44 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R5a2c And R5a2d Independently H, halogen, OH, -OR6 , -NHR6 , -NR6 R7 , C1 -C6 Alkyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl. Example III-46. The compound of any one of Examples III-44 to III-45 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R5a2c And R5a2d Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl. Examples III-47. The compound of Example III-29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 Is selected from the group consisting of: Examples III-48. The compound of Example III-29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 Is selected from the group consisting of:and. Examples III-49. The compound of Example III-29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 Is selected from the group consisting of:and. Example III-50. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system. Examples III-51. The compound of Example III-50 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein one of the A series is CR5a1 And another A is N. Example III-52. The compound of any one of Examples III-50 to III-51 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where each A2 Independently C (R5a2 )2 , NR5a2 Or O. Example III-53. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system, Which has the formulaWhere A2ab Selected from CR5a2 , C (R5a2a ) (R5a2b ), N, NR5a2 , O, S, or S (O)2 ; A2cd Selected from CR5a2 , C (R5a2c ) (R5a2d ), N, NR5a2 , O, S, or S (O)2 ; A2ef Selected from CR5a2 , C (R5a2e ) (R5a2f ), N, NR5a2 , O, S, or S (O)2 ; And A2gh Selected from CR5a2 , C (R5a2g ) (R5a2h ), N, NR5a2 , O, S, or S (O)2 ; A2ij Selected from CR5a2 , C (R5a2i ) (R5a2j ), N, NR5a2 , O, S, or S (O)2 ; Each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g , R5a2h , R5a2i And R5a2j Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g , R5a2h , R5a2i And R5a2j Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g , R5a2h , R5a2i And R5a2j A pendant oxygen group can be formed. Examples III-54. The compound of Example III-50 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 system. Example III-55. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system. Examples III-56. The compound of Example III-55 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein one of the A series is CR5a1 And another A is N. Example III-57. The compound of any one of Examples III-55 to III-56 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where each A2 Independently C (R5a2 )2 , NR5a2 Or O. Example III-58. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system, Which has the formulaWhere A2ab Selected from C (R5a2a ) (R5a2b ), NR5a2 , O, S, or S (O)2 ; A2cd Selected from C (R5a2c ) (R5a2d ), NR5a2 , O, S, or S (O)2 ; A2ef Selected from C (R5a2e ) (R5a2f ), NR5a2 , O, S, or S (O)2 ; And each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution; or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution; or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e And R5a2f A pendant oxygen group can be formed. Examples III-59. The compound of Example III-55 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R1 system. Example III-60. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system. Examples III-61. The compound of Example III-60 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein one of the A series is CR5a1 And another A is N. Example III-62. The compound of any one of Examples III-60 to III-61 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where each A2 Independently C (R5a2 )2 , NR5a2 Or O. Example III-63. The compound of any one of Examples III-1 to III-22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Where R1 system, Which has the formulaWhere A2ab Selected from CR5a2 , C (R5a2a ) (R5a2b ), N, NR5a2 , O, S, or S (O)2 ; A2cd Selected from CR5a2 , C (R5a2c ) (R5a2d ), N, NR5a2 , O, S, or S (O)2 ; A2ef Selected from CR5a2 , C (R5a2e ) (R5a2f ), N, NR5a2 , O, S, or S (O)2 ; And A2gh Selected from CR5a2 , C (R5a2g ) (R5a2h ), N, NR5a2 , O, S, or S (O)2 ; Each R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Independently H, D, halogen, OH, CN, -NO2 , -SR6 , -OR6 , -NHR6 , -NR6 R7 , -C (O) R6 , -S (O)2 R6 , -C (O) OR6 , -C (O) NR6 , C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH2 -C3 -C8 Cycloalkyl; where these C1 -C6 Alkyl, C2 -C6 Alkenyl, C4 -C8 Cycloalkenyl, C2 -C6 Alkynyl, C3 -C8 Cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH2 -C3 -C8 Cycloalkyl via D, -CN, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -NR6 C (O) OR6 , -NR6 C (O) R6 , NR6 C (O) NR6 , -NR6 C (O) R6 Or -NR6 S (O)2 R6 Substitution, or two R5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h Forms C with the atom to which it is attached3 -C8 Cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C3 -C8 Cycloalkyl and heterocyclyl via D, halogen, C1 -C6 Alkyl, -OR6 , -NH2 , -NH (C1 -C6 Alkyl), -N (C1 -C6 alkyl)2 , -S (O)2 -R6 , -COR6 , NR6 C (O) OR6 , -NR6 C (O) R6 , -NR6 C (O) NR6 Or -NR6 S (O)2 R6 Substitution, or two R's on the same carbon5a2a , R5a2b , R5a2c , R5a2d , R5a2e , R5a2f , R5a2g And R5a2h A pendant oxygen group can be formed. Example III-64. The compound of any one of Examples III-1 to III-63 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof Of whichDepartment contains A2 A single bond in a ring, thereby forming a saturated ring. Embodiment III-65. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of: . Embodiment III-66. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of: . Embodiment III-67. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of:Embodiment III-68. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of: . Embodiment III-69. A pharmaceutical composition comprising the compound of any one of Embodiments III-1 to III-68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer Structures or tautomers and pharmaceutically acceptable carriers. Example III-70. A method of treating or preventing a disease, disorder, or condition that is responsive to inhibition of an inflamed body, comprising administering an effective amount of a compound as in any one of Examples III-1 to III-68 Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, is an individual in need thereof for the treatment or prevention of the disease, disorder or condition. Embodiments III-71. The method of Embodiments III-70, wherein the disease, disorder, or condition is a responder to the inhibition of activation of the NLRP3 inflammasome. Embodiment III-72. The method of Embodiment III-70 or III-71, wherein the disease, disorder, or condition affects IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37 , IL-22, IL-33, and Th17 cells respond to the regulation of one or more. Embodiments III-73. The method of Embodiments III-70 or III-71, wherein the disease, disorder, or condition is responsive to the modulation of one or more of IL-1β and IL-18. Embodiment III-74. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system. Embodiments III-75. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition, or an autoimmune disease, disorder, or condition. Embodiment III-76. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a liver disease, disorder, or condition. Embodiment III-77. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the lung. Embodiment III-78. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a skin disease, disorder, or condition. Embodiment III-79. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system. Embodiment III-80. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is cancer, tumor, or other malignant disease. Embodiment III-81. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the renal system. Embodiment III-82. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the gastrointestinal tract. Embodiment III-83. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system. Embodiment III-84. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the endocrine system. Embodiment III-85. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS). Embodiment III-86. The method of any one of Embodiments III-70 to III-73, wherein the disease, disorder, or condition is selected from the group consisting of: constitutive inflammation, cryptopyrin-associated cycle syndrome (CAPS ), Mu-Werner's syndrome (MWS), familial cold-induced autoinflammation syndrome (FCAS), neonatal onset multi-system inflammatory disease (NOMID), auto-inflammatory disease, familial Mediterranean fever (FMF) ), TNF receptor-related periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Margid's syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA), single dual gene deficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency and Immune disorders (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune disorders (APLAID), iron granulocyte anemia with B-cell immune deficiency, periodic fever, developmental delay (SIFD), Schwert's syndrome, chronic Non-bacterial osteomyelitis (CNO), chronic recurrence Lesion osteomyelitis (CRMO) and synovitis, acne, impetigo, bone hypertrophy, osteoinflammatory syndrome (SAPHO), autoimmune diseases (including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis , Bessette's disease, Hughlen's syndrome, Schnitzler's syndrome), respiratory diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestos lung , Silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, metabolism Disease, type 2 diabetes, atherosclerosis, obesity, gout, pseudogout, eye disease, ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic Nephropathy, oxalate nephropathy, diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, skin inflammation, contact allergies, sunburn, joint inflammation, osteoarthritis, systemic adolescent characteristics Arthritis, adult-onset stear's disease, relapsing polychondritis, viral infection, alpha virus infection, ququs virus infection, Roche virus infection, flavivirus infection, dengue virus infection, zika virus Infection, influenza, HIV infection, pyogenic sweat glanditis (HS), skin disease caused by cysts, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, spinal dysplasia syndrome, leukemia, polymyositis, stroke, myocardial infarction , Graft-versus-host disease, hypertension, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Drusler syndrome, ischemic reperfusion injury , And any disease in an individual who has been determined to have a germline line or somatic non-silent mutation in NLRP3. Embodiment III-87. The method of Embodiment III-86, wherein the disorder is selected from the group consisting of bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, Metabolic syndrome, obesity, rheumatoid arthritis, liver disease, liver steatosis, fatty liver disease, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Embodiments III-88. The method of Embodiments III-87, wherein the disorder is non-alcoholic steatohepatitis (NASH). Embodiments III-89. The method of any one of Embodiments III-70 to III-88, wherein the treatment or prevention of the disease, disorder, or condition is performed on a mammal. Embodiments III-90. The method of Embodiments III-89, wherein the mammal is a human individual. Example III-91. A method for modulating the activity of a biological target, comprising exposing the biological target to a compound of any one of Examples III-1 to III-68, or a pharmaceutically acceptable salt thereof, before Drug, solvate, isomer, or tautomer. Embodiment III-92. The method according to embodiment III-91, wherein the biological target can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α , IL-37, IL-22, IL-33 and Th17 cells. Embodiment III-93. The method according to embodiment III-91, wherein the biological target can be selected from the group consisting of IL-1β and IL-18. Example III-94. A method for inhibiting the activation of an inflamed body, comprising exposing a biological target to a compound of any one of Examples III-1 to III-68 or a pharmaceutically acceptable salt, prodrug thereof , Solvate, hydrate, isomer or tautomer. Embodiment III-95. The method of Embodiment III-94, wherein the inflammatory system NLRP3 is inflamed. Example III-96. The method of Examples III-94 or III-95, wherein the inhibition of the inflammasome is related to IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL One or more of -22, IL-33 and Th17 cells are related. Embodiments III-97. The method of Embodiments III-96, wherein the inhibition of the inflammasome is associated with one or more of IL-1β and IL-18. Example III-98. A compound according to any one of Examples III-1 to III-68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof The use of a substance for the treatment of a disease, disorder or condition that is responsive to the inhibition of an inflammable body. Example III-99. A compound according to any one of Examples III-1 to III-68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof For the manufacture of a medicament for the treatment of a disease, disorder or condition that is responsive to the inhibition of an inflamed body.Examples The following examples are provided to illustrate the invention and should not be construed as limiting it. In these examples, all parts and percentages are by weight unless otherwise stated. The abbreviations in the examples are recorded below.abbreviation Examples 1 : Compound 1 Synthesis . ( N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H-pyrazole And [5,1-b] [1,3] oxazine-3-sulfonamidemethod A : N, N-Dimethylpyridin-4-amine (0.517 mmol, 0.063 g) was dissolved in THF (1.5 mL) and then di-t-butyl dicarbonate (0.492 mmol, 0.113 mL) was slowly added in THF ( 1.5 mL). After stirring for several minutes, a solution of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-amine (0.492 mmol, 0.085 g) in THF (1 mL) was added and The mixture was stirred for 30 min. Simultaneously, 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonium in THF (1mL) was treated with sodium hydride (0.492 mmol, 0.018 g). Amine (0.492 mmol, 100 mg) and stirred for 30 min. At this point, the two solutions were mixed and stirred for 18 h. Followed by NH4 The reaction was quenched with Cl (10 mL) and diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were then washed with water (10 mL) and concentrated. The resulting solid was suspended in MeOH (5 mL), filtered, and filtered by prep HPLC (10-40% MeCN: 10 mM aq.NH3 ) The filtrate was purified. The purified fractions were combined and concentrated to give N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) as a white solid) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Compound 1) (3.5 mg, 1.768%). [M + H]+ Experimental value 403.1 H-NMR (400 MHz; MeOD): δ 7.67 (s, 1H), 6.93 (d,J = 0.9 Hz, 1H), 6.93 (d,J = 0.9 Hz, 1H), 4.42 (t,J = 5.3 Hz, 2H), 4.42 (t,J = 5.3 Hz, 2H), 4.16 (t,J = 6.2 Hz, 2H), 4.16 (t,J = 6.2 Hz, 2H), 2.86 (t,J = 7.4 Hz, 4H), 2.86 (t,J = 7.4 Hz, 4H), 2.74-2.71 (m, 4H), 2.74-2.71 (m, 4H), 2.31-2.25 (m, 3H), 2.31-2.25 (m, 3H), 2.08-2.00 (m, 6H ), 2.08-2.00 (m, 6H).method B : TCPC Preparation In N2 Then, a solution of 2,4,6-trichloro-phenol (50 g, 250 mmol) and pyridine (20.5 mL, 250 mmol) in ether (800 mL) was cooled to -78 ° C. After cooling, a solid formed in the mixture. Slowly add SO to the mixture2 Cl2 (21 mL, 250 mmol). The reaction was then stirred overnight at r.t. The reaction mixture was filtered through a celite pad and rinsed with ether (300 mL). The ether solution was concentrated below 40 ° C. Purification of the residue by a silica gel column (hexane ~ PE) gave a colorless oilTCPC (55 g, yield 75%).1 H NMR (400 MHz, CDCl3 ): δ = 7.45 (s, 2H).step 1 Add 1,2-dihydro-pyrazol-3-one (4.0 g, 47.6 mmol) and K2 CO3 (23.0 g, 166.7 mmol) was heated to 130 ° C in DMF (80 mL). 1,3-Dibromopropane (11.6 g, 57.1 mmol) was added and the mixture was heated for 3 hr and then concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with EA (50 mL) and the combined organic layers were washed with brine (50 mL).2 SO4 Dry, filter and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 1/2) to produce 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine as a yellow oil ( 3.0 g, yield: 51%).1 H NMR (400 MHz, CDCl3 ): δ = 7.31 (d,J = 2.0 Hz, 1H), 5.48 (d,J = 2.0 Hz, 1H), 4.28 (t,J = 5.2 Hz, 2H), 4.18 (t,J = 6.2 Hz, 2H), 2.29-2.22 (m, 2H).step 2 To a solution of 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (3.0 g, 24.3 mmol) in MeCN (40 mL) at 0 ° C NBS (4.4 g, 24.7 mmol) was added and the reaction was stirred at room temperature for 2 hr. Filter the mixture and pass through a reversed-phase column (5%-95% H2 MeCN in O) was purified to give 3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (3.6 g, yield: 74 as a yellow solid) %).1 H NMR (400 MHz, CDCl3 ): δ = 7.30 (s, 1H), 4.36 (t,J = 5.2 Hz, 2H), 4.17 (t,J = 6.2 Hz, 2H), 2.30-2.24 (m, 2H).step 3 N at -78 ° C2 Downward solution of 3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (1.8 g, 8.9 mmol) in anhydrous THF (15 mL) Slowly add n-BuLi (2.5 M, 3.5 mL, 8.9 mmol) in hexane. After stirring for 20 minutes under cooling, slowly add ZnCl in ether at this temperature.2 (1 M, 8.9 mL, 8.9 mmol). The cold bath was removed and the reaction was stirred at r.t. for 1 hr. TCPC (2.6 g, 8.9 mmol) was then added at 0 ° C and stirred for 1 hr at r.t. Saturate the reaction with saturated NH4 The Cl solution (10 mL) was quenched and partitioned between water (80 mL) and EA (80 mL). The organic layer was washed with brine (80 mL),2 SO4 Dry and concentrate to give crude 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichloro- Phenyl ester, which was used in the next step without any purification.step 4 The 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichloro-phenyl ester (crude, about 8.9 mmol ), NH4 A mixture of OH (10 mL) and THF (10 mL) was stirred at 60 ° C overnight. The reaction was concentrated under reduced pressure until 10 mL of liquid remained. The remaining solution was acidified with 1 N HCl to pH = 5 and partitioned between EA (10 mL) and water (50 mL). With reversed phase columns (MeCN / H2 O) Purification of the aqueous layer to produce 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (650 mg, product Rate: 36% after 2 steps).1 HNMR (400 MHz, DMSO-d6 ): δ = 7.47 (s, 1H), 7.09 (brs, 2H), 4.40 (t,J = 5.2 Hz, 2H), 4.25 (t,J = 6.0 Hz, 2H), 2.22-2.14 (m, 2H). MS: m / z 203.9 (M + H+ ).step 5 To a solution of 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (120 mg, 0.6 mmol) in THF (10 mL) MeONa (40 mg, 0.7 mmol) was added to the mixture and stirred at rt for 20 min to produce a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (110 mg, 0.6 mmol) and TEA (120 mg, 1.2 To a solution of THF (10 mL) in THF (10 mL) was added triphosgene (120 mg, 0.4 mmol) in one portion at rt under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at r.t. for 20 min. Thereafter, the reaction solution was partitioned between EA (60 mL) and water (60 mL). The aqueous phase was acidified with concentrated HCl to pH = 5 and extracted with EA (60 mL). The organic layer was washed with water (50 mL) and brine (50 mL).2 SO4 Dry and concentrate until a white solid appears. The formed solid was collected by filtration and dried to give N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-yl) amine) as a white solid. (Amidino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (57 mg, yield: 22%).1 HNMR (400 MHz, DMSO-d6 ): δ = 10.46 (brs, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.42 (t,J = 5.2 Hz, 2H), 4.25 (t,J = 5.8 Hz, 2H), 2.79 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.6 Hz, 4H), 2.22-2.18 (m, 2H), 1.99-1.92 (m, 4H). MS: m / z 403.0 (M + H+ ).Examples 2 : Compound 2 Synthesis . N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethane) methanesulfonamide:To a solution of methanesulfonamide (95 mg, 1.0 mmol) in THF (5 mL) was added NaH (60%, 45 mg, 1.1 mmol) and stirred at room temperature for 10 min, resulting in a sodium salt suspension. To 1, 2, 3, 5, 6, 7-hexahydro-s-dicyclopentadienyl-4-ylamine (173 mg, 1.0 mmol) and TEA (0.5 mL, 3.5 mmol) in THF (10 To the solution in mL) was added triphosgene (120 mg, 0.4 mmol) in one portion and the mixture was stirred at room temperature under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 30 min. Thereafter, the reaction solution was partitioned between ethyl acetate (50 mL) and water (100 mL). The aqueous phase was filtered and acidified to pH = 5 with aq. HCl (1N). The formed solid was collected by filtration and dried to give N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-yl) amine) as a white solid. Fluorenyl) methanesulfonamide (130 mg, yield: 44%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.19 (brs, 1H), 8.13 (s, 1H), 6.96 (s, 1H), 3.26 (s, 3H), 2.82 (t,J = 7.2 Hz, 4H), 2.71 (t,J = 7.2 Hz, 4H), 2.03-1.94 (m, 4H). MS: m / z 295.0 (M + H+ ).Examples 3 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Thioaminomethyl ) -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) thiocarbamyl) -6,7-dihydro- Synthesis of 5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 To a solution of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (350 mg, 2 mmol) in THF (20 mL) was added sulfur light Gas (233 mg, 2 mmol) and TEA (612 mg, 6 mmol). The reaction mixture was stirred at room temperature overnight and then evaporated in vacuo. Dilute the residue in saturated NaHCO3 (50 mL) and extracted the aqueous phase with EA (50 mL × 3). Combine the organic extracts over anhydrous Na2 SO4 Dry and concentrate in vacuo to give 4-isocyanothio-1,2,3,5,6,7-hexahydro- as the crude products -Dicyclopentadienacene, which was used in the next step without further purification.step 2 To 6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazine-3-sulfonamide (60 mg, 0.3 mmol) in DMF (5 mL) was added with 4-isocyanothio-1,2,3,5,6, 7-hexahydro-s -Dicyclopentadiene benzene (64.5 mg, 0.3 mmol) and NaH (60% in mineral oil, 24 mg, 0.6 mmol). The reaction was stirred at room temperature for 2 hr (monitored by LC-MS) and by H2 O (20 mL) was quenched. The mixture was acidified from 1 M HCl to pH = 3 and extracted with EA (20 mL x 3). Combine the organic phases over anhydrous Na2 SO4 Dry and evaporate in vacuo. The residue was purified by pre-HPLC to give N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) thioamine as a white solid (Methylfluorenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (30 mg, yield: 24.2%).1 H NMR (400 MHz, DMSO-d6 ): δ = 7.62 (s, 1H), 7.21-6.96 (m, 2H), 4.40-4.35 (m, 2H), 4.11-4.08 (m, 2H), 2.80 (t,J = 7.2 Hz, 4H), 2.63-2.58 (m, 4H), 2.19-2.16 (m, 2H), 1.98-1.91 (m, 4H). MS: m / z 417.0 (M-H+ ).Examples 4 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -4,5,6,7- Tetrahydropyrazolo [1,5-a] Pyridine -3- Of sulfasalazine synthesis: The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -4,5,6,7-tetra Synthesis of Hydropyrazolo [1,5-a] pyridine-3-sulfonamide. step 1 N at -78 ° C2 Slowly add hexane to a solution of 3-bromo-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine (1 g, 5 mmol) in anhydrous THF (10 mL) N-BuLi (2.5 M, 2 mL, 5 mmol). After stirring for 20 minutes under cooling, slowly add ZnCl in ether at this temperature.2 (1 M, 5 mL, 5 mmol). The cold bath was removed and the reaction was stirred at room temperature for 1 hr. TCPC (1.8 g, 5 mmol) was then added and the reaction solution was stirred at room temperature for 1 hr. The reaction was partitioned between water (80 mL) and EA (80 mL). The organic layer was washed with brine (80 mL),2 SO4 Drying and concentrating to yield crude yellow 4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine-3-sulfonic acid 2,4,6-trichloro-phenyl ester , Which was used in the next step without any purification.step 2 4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine-3-sulfonic acid 2,4,6-trichloro-phenyl ester (crude, about 5 mmol), NH3. H2 A mixture of O (15 mL) and THF (15 mL) was stirred at 60 ° C overnight. The reaction was concentrated under reduced pressure. The remaining solution was acidified with 1 N HCl to pH = 5 and partitioned between EA (15 mL) and water (70 ml). The aqueous phase was purified by a reversed-phase column to give 4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine-3-sulfonamide (270 mg, yield) as a yellow solid. : 27% via 2 steps).1 H NMR (400 MHz, DMSO-d6 ): δ = 7.62 (s, 1H), 7.15 (brs, 2H), 4.08 (t,J = 6.0 Hz, 2H), 2.90 (t,J = 6.4 Hz, 2H), 1.98-1.92 (m, 2H), 1.83-1.77 (m, 2H). MS: m / z 201.9 (M + H+ ).step 3 This step is similar to N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro- General procedure for 5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 1). HNMR (400 MHz, DMSO-d 6): δ = 10.54 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 6.94 (s, 1H), 4.09 (t,J = 5.6 Hz, 2H), 2.97 (t,J = 6.4 Hz, 2H), 2.78 (t,J = 7.6 Hz, 4H), 2.57 (t,J = 7.6 Hz, 4H), 1.98-1.90 (m, 6H), 1.82-1.78 (m, 2H). MS: m / z 401.0 (M + H+ ).Examples 5 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -5 ', 7'- Dihydrospiro [ Oxetane -3,6'- Pyrazolo [5,1-b] [1,3] Oxazine ] -3'- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) carbamyl) -5 ', 7'-dihydrospiro Synthesis of [oxetane-3,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'-sulfamethoxamine.The title compound uses N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro- 5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 1) was prepared according to the general procedure.1 H NMR (400 MHz, DMSO-d 6): δ = 7.77 (s, 1H), 7.51 (s, 1H), 6.85 (s, 1H), 4.59 (s, 2H), 4.50 (d,J = 6.0 Hz, 2H), 4.43 (d,J = 6.4 Hz, 2H), 4.38 (s, 2H), 2.76 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.4 Hz, 4H), 1.94-1.90 (m, 4H). MS: m / z 445.0 (M + H+ ).Examples 6 : N-((2,6- Diisopropylphenyl ) Carbamate ) -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((2,6-diisopropylphenyl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- Synthesis of 3-sulfonamide.Suspend 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (0.123 mmol, 0.025 g) in THF (1 mL) and cool to 0 ° C. NaH (0.123 mmol, 2.95 mg) was added and the mixture was stirred for 5 min. Then 2-isocyanato-1,3-diisopropylbenzene (0.123 mmol, 0.026 mL) was added and the mixture was stirred at room temperature for 2 h. At this time, the reaction was quenched with water and the organic solvent was evaporated. The reaction was then acidified with HCl and the white precipitate was filtered, washed with water and dried to produce N-((2,6-diisopropylphenyl) aminomethylamidino) -6,7-dihydro-5H-pyrazole And [5,1-b] [1,3] oxazine-3-sulfonamide (38 mg, 76%).1 H-NMR (400 MHz; DMSO-d6 ): δ 10.60 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.24 (t,J = 7.7 Hz, 1H), 7.12 (d,J = 7.7 Hz, 2H), 4.46-4.44 (m, 2H), 4.11 (dd,J = 7.5, 4.7 Hz, 2H), 2.91 (t,J = 6.9 Hz, 2H), 2.23-2.20 (m, 2H), 1.13-1.01 (m, 12H). MS: m / z 407 (M + H+ ).Examples 7 : N-((4- chlorine -2,6- Diisopropylphenyl ) Carbamate ) -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((4-chloro-2,6-diisopropylphenyl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 Synthesis of oxazine-3-sulfonamide.Dissolve 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (0.105 mmol, 0.021 g) in THF (2 mL) and add Treat with NaH (0.105 mmol, 4.21 mg) at ℃. After a few minutes, 5-chloro-2-isocyanato-1,3-diisopropylbenzene (0.105 mmol, 25 mg) was added and the mixture was stirred over the weekend. The reaction was then quenched with water and the solvent was reduced to about 1/3 of the initial volume. The reaction was then acidified with 1M HCl and the fine white precipitate was filtered, washed with water and dried to give N-((4-chloro-2,6-diisopropylphenyl) aminomethyl) -6,7-di Hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (23.7 mg, 51.1%).1 H-NMR (400 MHz; DMSO-d6 ): δ 10.70 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.15 (s, 2H), 4.45 (dd,J = 5.4, 4.8 Hz, 2H), 4.11 (t,J = 6.1 Hz, 2H), 3.62-3.59 (m, 3H), 2.93-2.86 (m, 2H), 2.24-2.20 (m, 2H), 1.78-1.75 (m, 3H), 1.11-1.01 (m, 13H ). MS: m / z 442 (M + H+ ).Examples 8 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -6,6- Dimethyl -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,6-dimethyl-6 Synthesis of 7,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 PPh at 0 ℃3 (252.0 g, 961.5 mmol) in a suspension in acetonitrile (600 mL) was added dropwise to Br2 (49.3 mL, 961.5 mmol) in acetonitrile (200 mL), followed by 2,2-dimethyl-propane-1,3-diol (50.0 g, 480.8 mmol). The reaction mixture was heated to 85 ° C and refluxed for 16 hr. The solvent was removed in vacuo. The residual solid was washed with (PE / EA = 3/1, 300 mL) and filtered. The filtrate was concentrated and distilled to give 1,3-dibromo-2,2-dimethyl-propane (45.0 g, yield: 41%) as a colorless oil.1 HNMR (300 MHz, CDCl3 ): δ = 3.42 (s, 4H), 1.18 (s, 6H).step 2 Add 1,2-dihydro-pyrazol-3-one (25.0 g, 297.6 mmol) and K2 CO3 (144.0 g, 1041.7 mmol) was heated to 120 ° C in DMF (700 mL). 1,3-Dibromo-2,2-dimethyl-propane (82.0 g, 357.1 mmol) was added and the mixture was heated for 24 hr. The solvent was removed in vacuo. Partition the residue in EA / H2 O (200 mL / 500 mL) and separate the layers. The aqueous layer was extracted with EA (200 mL) and the combined organic layers were washed with brine (100 mL).2 SO4 Dry and concentrate. The residue was cooled to 5 ° C and washed with PE (100 mL) to give 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1, as a yellow solid 3] Oxazine (14.0 g, yield: 31%).1 HNMR (300 MHz, CDCl3 ): δ = 7.32 (s, 1H), 5.48 (s, 1H), 3.87 (s, 2H), 3.84 (s, 2H), 1.13 (s, 6H).step 3-5 The three steps are similar to N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di General procedure for hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 1).step 6 To 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (400 mg, 1.7 mmol) To the suspension in THF (10 mL) was added MeONa (190 mg, 3.5 mmol) and the mixture was stirred at room temperature for 20 min, resulting in a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (300 mg, 1.7 mmol) and TEA (530 mg, 5.2 mmol) in THF (15 mL) was added triphosgene (210 mg, 0.7 mmol) in one portion and the mixture was stirred at room temperature under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 16 hr. Thereafter, the reaction solution was partitioned between EA (50 mL) and water (150 mL). Filter the water phase and pass N2 Bubbling for 5 min, followed by acidification with concentrated HCl to pH = 5. After the addition of MeCN (50 mL), the solid formed was dissolved. The mixture was concentrated at 40 ° C to remove MeCN. The formed solid was collected by filtration and dried to give N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-yl) amine) as a white solid. Fluorenyl) -6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (320 mg, yield : 43%).1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.49 (s, 1H), 7.90 (s, 1H), 7.64 (s, 1H), 6.93 (s, 1H), 4.14 (s, 2H), 3.88 (s, 2H), 2.78 (t,J = 7.2 Hz, 4H), 2.58 (t,J = 7.2 Hz, 4H), 1.98-1.90 (m, 4H), 1.02 (s, 6H). MS: m / z 431.0 (M + H+ ).Examples 9 : 6,6- Dimethyl -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of sulfonamide The following shows another method for synthesizing 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 To ClSO at 0 ° C3 H (25 mL) was added in portions of 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (3.0 g, 19.7 mmol) . After stirring at 80 ° C for 16 hr, the reaction mixture was added dropwise to ice water (250 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (50 mL),2 SO4 Dry and concentrate. The residue was cooled to 5 ° C and washed with PE / EA (5/1, 30 mL) to give 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1 as a yellow solid -b] [1,3] oxazine-3-sulfosulfanyl chloride (2.4 g, yield: 49%).1 HNMR (300 MHz, CDCl3 ): δ = 7.79 (s, 1H), 4.16 (s, 2H), 3.90 (s, 2H), 1.20 (s, 6H).step 2 To 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride (2.2 g, 8.8 mmol) in THF (18 mL) with NH3 .H2 O (10 mL). After stirring at 60 ° C for 1 hr, the reaction mixture was concentrated to dryness. The residue was diluted with MeOH (20 mL) and acidified from aq. HCl (2 N) to pH = 5. With reversed phase columns (0%-60% H2 MeCN in O) purified the resulting solution to produce 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3 as a yellow solid -Ammonium sulfonate (1.6 g, yield: 79%).Examples 10 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -6- Hydroxyl -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-hydroxy-6,7-di Synthesis of hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 To a solution of 1,3-dibromo-propan-2-ol (42.5 g, 0.19 mol) and DHP (33 g, 0.38 mol) in DCM (300 mL) was added TsOH (3.6 g, 0.019 mol) in portions. The mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated and the residue was purified by a silica gel column (PE / EA = 50/1) to give 2- (2-bromo-1-bromomethyl-ethoxy) -tetrahydro-pyran as a colorless oil. (34 g, yield: 60%).1 H NMR (300 MHz, DMSO-d6 ): δ = 4.80-4.79 (m, 1H), 4.04-3.90 (m, 2H), 3.72-3.52 (m, 5H), 1.87-1.55 (m, 6H).step 2 Add 2- (2-bromo-1-bromomethyl-ethoxy) -tetrahydro-pyran (17 g, 56.3 mmol), 1,2-dihydro-pyrazol-3-one (4 g, 47 mmol) and K2 CO3 A mixture of (23 g, 165 mmol) in DMF (250 mL) was stirred at 100 ° C overnight. The solvent was removed under reduced pressure. Partition the residue between EA (200 mL) and water (200 ml). The aqueous phase was extracted with EA (200 ml). The organic layers were combined, washed with water (100 mL) and brine (100 mL), and washed with Na2 SO4 Dry and concentrate. The residue was purified by a silica gel column (EA) to give 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1- b] [1,3] oxazine (4.9 g, yield: 46%).1 H NMR (300 MHz, DMSO-d6 ): δ = 7.34 (s, 1H), 5.51 (s, 1H), 4.89-4.83 (m, 1H), 4.36-4.24 (m, 4H), 3.93-3.88 (m, 1H), 3.59-3.54 (m , 1H), 1.79-1.69 (m, 3H), 1.65-1.51 (m, 4H). MS: m / z 224.9 (M + H+ ).step 3 N at 0 ° C2 Downward 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (5.1 g, 22.8 mmol ) In the solution in MeCN, add NBS in two portions. The reaction was then stirred at room temperature for 1 hr. The reaction was partitioned between EA (100 mL) and water (200 mL). The organic layer was washed with water (100 mL) and brine (100 mL),2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give 3-bromo-6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro- as a yellow solid 5H-pyrazolo [5,1-b] [1,3] oxazine (5.6 g, yield: 81%).1 H NMR (300 MHz, DMSO-d6 ): δ = 7.33 (s, 1H), 4.88-4.82 (m, 1H), 4.48-4.18 (m, 5H), 3.88-3.75 (m, 1H), 3.58-3.53 (m, 1H), 1.84-1.51 (m, 7H). MS: m / z 303.0 (M + H+ ).step 4 N at -78 ° C2 Downward 3-bromo-6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (2 g, 6.6 mmol) in anhydrous THF (20 mL) was slowly added n-BuLi (2.5 M, 2.6 mL, 6.6 mmol) in hexane. After stirring for 20 minutes under cooling, slowly add ZnCl in ether at this temperature.2 (1 M, 6.6 mL, 6.6 mmol). The cold bath was removed and the reaction was stirred at room temperature for 1 hr. TCPC (2 g, 6.6 mmol) was then added and the mixture was stirred at room temperature for 1 hr. The reaction was partitioned between water (100 mL) and EA (100 mL). The organic layer was washed with brine (100 mL),2 SO4 Dry and concentrate to give crude 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 as a yellow gel ] Oxazine-3-sulfonic acid 2,4,6-trichloro-phenyl ester, which was used in the next step without any purification.step 5 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2, 4,6-trichloro-phenyl ester (crude, about 6.6 mmol), NH4 A mixture of OH (20 mL) and THF (20 mL) was stirred at 60 ° C overnight. The reaction was concentrated under reduced pressure until 10 mL of liquid remained. The remaining solution was acidified with 1 N HCl to pH = 5 and extracted with EA (100 mL x 5). Combine the organic layers over Na2 SO4 Dry and concentrate to give crude 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 as a yellow gel ] Oxazine-3-sulfonamide, which was used in the next step without any purification. MS: m / z 304.1 (M + H+ ).step 6 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Crude, 6.6 mmol) in THF / H2 To the solution in O / EtOH (50 mL / 10 mL / 50 mL) was added concentrated HCl (10 mL) and stirred at room temperature overnight. The reaction was concentrated under reduced pressure. With reversed phase columns (MeCN / H2 O) Purification of the residue to give 6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (290 mg, yield: 21% over 3 steps).1 H NMR (300 MHz, DMSO-d6 ): δ = 7.48 (s, 1H), 7.11 (brs, 2H), 5.65 (brs, 1H), 4.30-4.20 (m, 4H), 3.96-3.92 (m, 1H). MS: m / z 220.1 (M + H+ ).step 7 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (63.1 mg, 0.365 mmoL) and TEA (0.203 ml, 1.1 mmoL) in THF (5 To the solution in ml) was added triphosgene (43.7 mg, 0.146 mmoL), and the mixture was stirred at room temperature for 10 min. In another round bottom flask, 6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (80 mg, 0.365 mmoL) in a solution in THF (5 ml) was added MeONa (21.7 mg, 0.401 mmoL) and the mixture was stirred at room temperature for 20 min. The prepared 4-isocyanato-1,2,3,5,6,7-hexahydro-s-dicyclopentadiene acene was filtered to remove the resulting precipitate and the filtrate was added to a salt containing sulfonamide In another flask. The reaction was checked by TLC and after 20 min was quenched with added water (30 mL). The aqueous phase was washed with EA (20 mL) and filtered later. Acidify the filtrate to pH = 3 ~ 4. The resulting solid was collected by filtration to give N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) as a white solid) -6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (15 mg, yield: 10%).1 H NMR (400 MHz, DMSO-d6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.67 (s, 1H), 4.34 (s, 3H), 4.24 (dd,J = 4.0, 3.2 Hz, 1H), 3.96 (d,J = 12.4Hz, 1H), 2.78 (t,J = 7.2Hz, 4H), 2.60 (t,J = 7.6Hz, 4H), 1.98-1.93 (m, 4H). MS: m / z 419.1 (M + H+ ).Examples 11 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -5,6,7,8- Tetrahydropyrazolo [5,1-b] [1,3] Oxazepine -3- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -5,6,7,8-tetra Synthesis of Hydropyrazolo [5,1-b] [1,3] oxazepine-3-sulfonamide. step 1 Add 1,2-dihydro-pyrazol-3-one (3.0 g, 35.7 mmol) and K2 CO3 (17.0 g, 125.0 mmol) was heated to 130 ° C in DMF (100 mL). 1,4-Dibromo-butane (9.3 g, 42.9 mmol) was added and the mixture was heated and held for 16 hr. The solvent was removed in vacuo. Partition the residue in EA / H2 O (50 mL / 80 mL) and separate the layers. The aqueous layer was extracted with EA (50 mL), and the combined organic layers were washed with brine (50 mL).2 SO4 Dry and concentrate. Purification of the residue by a silica gel column (PE / EA = 1/1) yielded a colorless oily 5,6,7,8-tetrahydro-4-oxa-1,8a-diaza-chamomile (1.3 g, yield: 27%).1 H NMR (300 MHz, CDCl3 ): δ = 7.24 (d,J = 1.5 Hz, 1H), 5.69 (d,J = 1.5 Hz, 1H), 4.25-4.20 (m, 2H), 4.06 (t,J = 5.1 Hz, 2H), 2.07-2.03 (m, 2H), 1.91-1.84 (m, 2H).step 2-5 The four steps are similar to N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di General procedure for hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 3).1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.60 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 6.94 (s, 1H), 4.22-4.16 (m, 4H), 2.79 (t,J = 7.6 Hz, 4H), 2.58 (t,J = 7.2 Hz, 4H), 2.03-1.90 (m, 6H), 1.80-1.70 (m, 2H). MS: m / z 417.0 (M + H+ ).Examples 12 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H- Synthesis of pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 Add 1,2-dihydro-pyrazol-3-one (2.0 g, 23.8 mmol) and K2 CO3 (11.5 g, 83.3 mmol) was heated to 120 ° C in DMF (60 mL). 1,3-Dibromo-butane (6.2 g, 28.6 mmol) was added and the mixture was heated and held for 16 hr. The solvent was removed in vacuo. Partition the residue in EA / H2 O (50 mL / 80 mL) and separate the layers. The aqueous layer was extracted with EA (50 mL), and the combined organic layers were washed with brine (50 mL).2 SO4 Dry and concentrate. Purification of the residue by a silica gel column (PE / EA = 5/1 to 1/1) yielded 7-methyl-6,7-dihydro-5H-pyrazolo [5,1-b as a yellow oil ] [1,3] oxazine (1.3 g, yield: 40%) and 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 as a yellow solid ] Oxazine (500 mg, yield: 15%). 7-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine:1 HNMR (400 MHz, CDCl3 ): δ = 7.32 (d,J = 2.0 Hz, 1H), 5.45 (d,J = 1.6 Hz, 1H), 4.36-4.31 (m, 2H), 4.24-4.18 (m, 1H), 2.34-2.27 (m, 1H), 2.02-1.94 (m, 1H), 1.59 (d,J = 6.0 Hz, 3H). 5-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine:1 HNMR (400 MHz, CDCl3 ): δ = 7.30 (d,J = 1.6 Hz, 1H), 5.45 (d,J = 2.0 Hz, 1H), 4.38-4.30 (m, 1H), 4.25-4.20 (m, 1H), 4.15-4.08 (m, 1H), 2.19-2.03 (m, 2H), 1.46 (d,J = 6.4 Hz, 3H).step 2-5 The four steps are similar to N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di General procedure for hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 1).1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.47 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 6.94 (s, 1H), 4.53-4.32 (m, 3H), 2.79 (t,J = 7.2 Hz, 4H), 2.58 (t,J = 7.2 Hz, 4H), 2.38-2.31 (m, 1H), 1.99-1.91 (m, 5H), 1.45 (d,J = 6.0 Hz, 3H). MS: m / z 417.0 (M + H+ ).Examples 13 : 6- fluorine -N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows 6-fluoro-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di Synthesis of hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 N at -78 ° C2 6-Hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (100 mg, 0.46 mmol) in DCM (5 To the solution in mL) was added DAST (148 mg, 0.92 mmol). The reaction was then stirred at room temperature overnight. The reaction with H2 O (20 mL) was quenched and partitioned between DCM (40 mL) and water (20 mL). Via Na2 SO4 The organic layer was dried and concentrated. The residue was purified by a reversed-phase column (MeCN / H2O) to give 6-fluoro-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine as a white solid Pyridine-3-sulfonate (18 mg, yield: 18%). MS: m / z 222.1 (M + H+ ).step 2 This step is similar to N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro- General procedure for 5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 1).1 H NMR (400 MHz, DMSO-d 6): δ = 10.58 (s, 1H), 8.00 (s, 1H), 7.69 (s, 1H), 6.93 (s, 1H), 5.58 (d,J = 44.0 Hz, 1H), 4.75 (t,J = 12.0 Hz, 1H), 4.59-4.37 (m, 3H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.97-1.90 (m, 4H). MS: m / z 421.0 (M + H+ ).Examples 14 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -6- Methoxy -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6,7 -Synthesis of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 3-Bromo-6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (4.6 g , 15.2 mmol) in THF / H2 To the solution in O / EtOH (50 mL / 10 mL / 50 mL) was added concentrated HCl. The reaction was stirred at room temperature for 2 hr. The reaction solution was concentrated. The residue was saturated with NaHCO3 Solution treatment. The formed solid was collected by filtration to give 3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (2.76 g) as a white solid. , Yield: 84%).1 H NMR (300 MHz, DMSO-d6 ): δ = 7.36 (s, 1H), 5.59 (brs, 1H), 4.28-4.18 (m, 4H), 3.95-3.90 (m, 1H).step 2 3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (1.2 g, 5.5 mmol) Add NaH (60% in mineral oil, 263 mg, 6.6 mmol) to the solution. Place the reaction at room temperature under N2 Stir for 1 hr. MeI (940 mg, 6.6 mmol) was then added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (60 mL) and extracted with EA (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL).2 SO4 Dry and concentrate. With reversed phase columns (MeCN / H2 O) Purification of the residue to give 3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (1 g , Yield: 78%).1 H NMR (300 MHz, CDCl3 ): δ = 7.34 (s, 1H), 4.53-4.48 (m, 1H), 4.27-4.18 (m, 3H), 3.94-3.93 (m, 1H), 3.49 (s, 3H). MS: m / z 232.9 (M + H+ ).step 3 ~ 5 These steps are similar to N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro General procedure for -5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 1).1 H NMR (400 MHz, DMSO-d 6): δ = 10.47 (s, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.65 (d,J = 11.6 Hz, 1H), 4.37 (d,J = 11.2 Hz, 1H), 4.24-4.22 (m, 2H), 4.06 (s, 1H), 3.34 (overlap, 3H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H). MS: m / z 433.0 (M + H+ ).Examples 15 : N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -5- methyl -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -5-methyl-6,7- Synthesis of Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide.The title compound uses N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro- 5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (Example 1) was prepared according to the general procedure.1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.51 (s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.94 (s, 1H), 4.60-4.56 (m, 1H), 4.13-4.08 (m, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.59 (t,J = 6.8 Hz, 4H), 2.28-2.24 (m, 1H), 1.98-1.93 (m, 5H), 1.38 (d,J = 6.0 Hz, 3H). MS: m / z 417.0 (M + H+ ).Examples 16 : N-((8- chlorine -1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -6,7- Dihydro -5H- Pyrazolo [5,1-b] [1,3] Oxazine -3- Synthesis of Sulfonamide The following shows N-((8-chloro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di Synthesis of hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-amine (2.332 mmol, 404 mg) and NCS (2.332 mmol, 0.311 g) in DCM (5mL) And stir overnight. The mixture was then partitioned between water (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were then subjected to Na2 SO4 Dry, filter, and concentrate to give 1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-amine (2.332 mmol, 404 mg) as a brown solid without Purified and used. MS: m / z 209 (M + H+ ).step 2 Dissolve N, N-dimethylpyridin-4-amine (0.481 mmol, 0.059 g) in THF (1.5 mL) and then slowly add di-t-butyl dicarbonate (0.481 mmol, 0.111 mL) in THF ( 1.5 mL). After stirring for several minutes, 8-chloro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-amine (0.481 mmol, 100 mg) was added to THF (1 mL) The solution was stirred and the mixture was stirred for 30 min. At the same time, 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (0.481 mmol, 0.098 g) in THF (1 mL) was hydrogenated Treat with sodium (0.481 mmol, 0.012 g) and stir for 30 min. At this point, the two solutions were mixed and stirred for 18 h. The reaction was then quenched with saturated NH4Cl (10 mL) and diluted with EtOAc (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were then washed with water (20 mL) and concentrated. The resulting solid was suspended in MeOH: water (10: 1, 10 mL), the red solid was filtered and discarded. The filtrate was concentrated and purified by preparative HPLC (10-40% MeCN: 10 mM NH3 water). The purified fractions were combined and concentrated to give N-((8-chloro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) as a white solid Carboxamidine) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (5.8 mg, 2.76%).1 H-NMR (400 MHz; DMSO-d6 ): δ 7.88-7.85 (m, 1H), 7.55 (s, 1H), 4.42-4.39 (m, 2H), 4.11-4.08 (m, 2H), 2.85-2.82 (m, 4H), 2.71 (t, J = 7.4 Hz, 4H), 2.22-2.16 (m, 2H), 2.04-1.97 (m, 4H). MS: m / z 437 (M + H+ ).Examples 17 : 4- fluorine -N-((1,2,3,5,6,7- Hexahydro -s- Dicyclopentadiene -4- base ) Carbamate ) -4,5,6,7- Tetrahydropyrazolo [1,5-a] Pyridine -3- Synthesis of Sulfonamide The following shows 4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -4,5,6 Synthesis of 7,7-tetrahydropyrazolo [1,5-a] pyridine-3-sulfonamide. step 1 To a solution of 4-bromo-2H-pyrazole-3-carboxylic acid ethyl ester (8.0 g, 36.4 mmol) in DMF (80 mL) was added K2 CO3 (10 g, 72.8 mmol) and ethyl 4-bromo-butyrate (10 g, 54.8 mmol), and then the suspension was stirred overnight. The reaction was quenched with the addition of EA (200 mL) and water (200 mL). The organic layer was separated. The aqueous layer was extracted with EA (200 mL). The organic layers were combined and washed with water (300 mL x 3), brine (300 mL), and2 SO4 dry. The solution was concentrated in vacuo. The residue was purified by a silica gel column (PE / EA = 10/1) to give 4-bromo-2- (3-ethoxycarbonyl-propyl) -2H-pyrazole-3-carboxylic acid ethyl as a colorless oil. Ester (6.7 g, yield: 55.4%). MS: m / z 332.8 (M + H+ ).step 2 To a solution of 4-bromo-2- (3-ethoxycarbonyl-propyl) -2H-pyrazole-3-carboxylic acid ethyl ester (6.7 g, 20.2 mmol) in THF (120 mL) at 0 ° C NaH (1.2 g, 30.3 mmol) was added and the mixture was then heated at reflux overnight. When the reaction is complete, the reaction is saturated with NH4 Aqueous Cl (20 mL) was quenched. The aqueous phase was extracted with EA (100 mL x 2). The extract was washed with brine (100 mL),2 SO4 Dry and concentrate to give 3-bromo-4- pendantoxy-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine-5-carboxylic acid ethyl ester as a white solid ( 5.2 g, yield: 90%). MS: m / z 286.9 (M + H+ ).step 3 3-Bromo-4-oxo-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine-5-carboxylic acid ethyl ester (5.2 g, 15.7 mmol) in DMSO ( 200 mL) and water (5 mL) was added to NaCl (5.5 g, 94 mmol), and the mixture was heated to 150 ° C for 2 hr. After cooling to room temperature, the reaction was diluted with EA (200 mL) and water (200 mL). The organic layer was separated. The aqueous layer was extracted with EA (200 mL). The combined organic layers were washed with water (300 mL x 3), brine (300 mL) and washed with Na2 SO4 dry. The solution was concentrated in vacuo. The residue was purified by a silica gel column (PE / EA = 5/1) to give 3-bromo-6,7-dihydro-5H-pyrazolo [1,5-a] pyridine-4- as a white solid. Ketone (2.6 g, yield: 66%).1 H NMR (400 MHz, DMSO-d6 ): δ = 7.55 (s, 1H), 4.40 (t,J = 6.0 Hz, 2H), 2.72 (t,J = 6.4 Hz, 2H), 2.36-2.40 (m, 2H).step 4 A solution of 3-bromo-6,7-dihydro-5H-pyrazolo [1,5-a] pyridin-4-one (1.6 g, 7.36 mmol) in MeOH (20 mL) at 0 ° C. Add NaBH4 (1.4 g, 12.8 mmol), and the mixture was stirred at room temperature for 2 hr. When the reaction was complete, the reaction was evaporated to remove MeOH. Partition the residue between EA (50 mL) and water (50 mL). The organic layer was separated. The aqueous layer was extracted with EA (50 mL). The combined organic layers were washed with brine (30 mL) and2 SO4 dry. The solution was concentrated to give 3-bromo-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridin-4-ol (1.4 g, yield: 88%) as a white solid. MS: m / z 216.9 (M + H+ ).step 5 3-Bromo-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridin-4-ol (1.4 g, 6.5 mmol) in DCM (30 mL) at -60 ° C To the solution was added DAST (2.1 g, 13 mmol). The solution was slowly warmed to room temperature and stirred at room temperature for 2 hr. When the reaction was complete, DCM (50 mL) and water (50 mL) were added to the mixture. The organic layer was separated. The aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with brine (50 mL),2 SO4 Dry and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 5/1) to give 3-bromo-4-fluoro-4,5,6,7-tetrahydro-pyrazolo [1,5- a] Pyridine (830 mg, yield: 59%).1 H NMR (400 MHz, DMSO-d6 ): δ = 7.50 (s, 1H), 5.60 (dt,J = 51.2, 2.8 Hz, 1H), 4.28-4.32 (m, 1H), 3.87-3.94 (m, 1H), 2.26-2.40 (m, 2H), 1.92-2.00 (m, 2H).step 6 N at -78 ° C2 3-Bromo-4-fluoro-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine (0.5 g, 2.3 mmol) in anhydrous THF (5 mL) under protection Slowly add n-BuLi (0.92 mL, 2.3 mmol, 2.5 M) in hexane. After stirring at this temperature for 20 min, slowly add ZnCl in ether at this temperature.2 (2.3 mL, 2.3 mmol, 1 M). The cold bath was removed and the reaction was stirred at room temperature for 1 hr. TCPC (0.68 g, 2.3 mmol) was added to the mixture at 0 ° C and the mixture was stirred at room temperature for 1 hr. Saturate the reaction with saturated NH4 The Cl solution (2 mL) was quenched and partitioned between water (20 mL) and EA (20 mL). The organic layer was washed with brine (80 mL),2 SO4 Dry and concentrate to give crude 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichloro- Phenyl ester. The crude was dissolved in THF (5 mL) and NH was added3. H2 O (5 mL) and then heated to 60 ° C overnight. When the reaction is completed, the reaction solution is concentrated to remove the solvent. The residue was acidified with 1 N HCl to pH = 5 and partitioned between EA (20 mL) and water (20 mL). The organic layer was separated. The aqueous layer was extracted with EA (20 mL). The combined organic layers were washed with brine (30 mL),2 SO4 Dry and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 2/1) to give 4-fluoro-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine- as a yellow solid Ammonium 3-sulfonate (0.17 g, yield: 34%). MS: m / z 220.0 (M + H+ ).step 7 4-Fluoro-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridine-3-sulfonamide (75 mg, 0.34 mmol) in THF (2 mL) MeONa (22 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 20 min, resulting in a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (59 mg, 0.34 mmol) and TEA (69 mg, 0.68 To a solution of THF (3 mL) in THF (3 mL) was added triphosgene (141 mg, 0.14 mmol) in one portion and the mixture was stirred at room temperature under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 1 hr. Thereafter, the reaction solution was partitioned between EA (15 mL) and water (15 mL). The aqueous phase was separated and acidified to pH = 5 with 1M HCl. The resulting solid was collected by filtration and air-dried to give 4-fluoro-N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-yl) as a white solid ) Carboxamido) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-3-sulfonamide (45 mg, yield: 31.4%).1 H NMR (400 MHz, DMSO-d6 ): δ = 10.67 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 6.08 (d,J = 49.2 Hz, 1H), 4.35-4.37 (m, 1H), 4.05-4.08 (m, 1H), 2.78 (t,J = 6.8 Hz, 4H), 2.55 (t,J = 6.8 Hz, 4H), 1.92-2.29 (m, 8H). MS: m / z 419.0 (M + H+ ).Examples 18 The following shows ((6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) ((1,2,3,5,6 Synthesis of 7-Hexahydro-s-dicyclopentadienyl-4-yl) carbamidine) sulfonamide sodium. step 1 : Add 1,2-dihydro-pyrazol-3-one (53.0 g, 630.9 mmol) and K2 CO3 (305.0 g, 2210.1 mmol) was heated to 130 ° C in DMF (1 L). 1,3-Dibromopropane (140.0 g, 693.1 mmol) was added and the mixture was heated for 8 hr and then concentrated. The residue was partitioned between EA (200 mL) and water (500 mL) and the layers were separated. The aqueous layer was extracted with EA (150 mL x 8), and the combined organic layers were washed with brine (300 mL),2 SO4 Dry, filter and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 3/1) to produce 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine as a yellow oil ( 32.0 g, yield: 41%).1 H NMR (400 MHz, CDCl3 ): δ = 7.31 (d,J = 2.0 Hz, 1H), 5.48 (d,J = 2.0 Hz, 1H), 4.28 (t,J = 5.2 Hz, 2H), 4.18 (t,J = 6.2 Hz, 2H), 2.29-2.22 (m, 2H).step 2 : To ClSO at 0 ° C3 H (380 mL) was added dropwise 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (64.0 g, 516.1 mmol). After stirring at 80 ° C for 16 hr, the reaction mixture was added dropwise to a mixture of ice water / EA (4 L / 1.5 L). The layers were separated and the aqueous layer was extracted with EA (300 mL x 2). The combined organic layers were washed with brine (500 mL),2 SO4 Dry and concentrate. The residue was washed with PE (200 mL) to give 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride (73.0 g) as a yellow solid , Yield: 63%).step 3 : To a solution of 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride (73.0 g, 328.8 mmol) in THF (430 mL) Add NH3 .H2 O (180 mL). After stirring at 60 ° C for 16 hr, the reaction mixture was concentrated to dryness. The residue was washed with aq.HCl (0.2 M, 110 mL), H2 O (40 mL) was washed and dried to give 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (52.0) as a yellow solid g, yield: 78%).1 HNMR (300 MHz, DMSO-d 6 ): δ = 7.47 (s, 1H), 7.08 (s, 2H), 4.40 (t,J = 5.1 Hz, 2H), 4.10 (t,J = 6.0 Hz, 2H), 2.23-2.15 (m, 2H).step 4 : To 1, 2, 3, 5, 6, 7-hexahydro-s-dicyclopentadienyl-4-ylamine (15.0 g, 87 mmol) and TEA (13.3 mL, 95.4) at 0 ~ 5 ℃ mmol) in THF (300 mL) was added triphosgene (8.5 g, 28.6 mmol) in one portion and the mixture was heated at 70 ° C. under N2 Stir for 1 hour. The reaction mixture was then filtered through diatomaceous earth. Wash the filter cake with 30 mL of PE. The filtrate was concentrated to dryness and dissolved in 100 mL of n-hexane. The mixture was filtered through a silicone pad. The filtrate was concentrated to dryness to give 4-isocyano-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene (14.6 g, yield: 84 as a pink oil). %). Suspension of 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (14.3 g, 70.4 mmol) in MeOH (500 mL) The solution was stirred at 80 ° C until a clear solution was obtained, then MeONa (3.8 g, 70.4 mmol) was added and the mixture was stirred for 5 min. The solution was concentrated to dryness and the residue was co-evaporated with MeCN (100 mL). The residual solid was suspended in MeCN (320 mL) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene (14.6 g, 73.3 mmol ). The mixture was stirred at room temperature for 16 hours and filtered. The filter cake was triturated with EtOH (250 mL), PE / EA (5/1, 250 mL) to produce the product. Dissolve the product in H2 O (200 mL) and concentrated to dryness to give ((6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonate Fluorenyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylfluorenyl) sulfonamide (24.5 g, yield: 82 %).1 HNMR (400 MHz, D2 O): δ = 7.64 (s, 1H), 7.02 (s, 1H), 4.40 (t,J = 5.2 Hz, 2H), 4.11 (t,J = 6.0 Hz, 2H), 2.83 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 2.28-2.22 (m, 2H), 2.04-1.96 (m, 4H). MS: m / z 403.1 (M + H+ ).Examples 19 The following shows 1-((1,2,3,5,6,7-hexahydro-s- Dicyclopentadiene -4-yl))-3- (2,3-dihydro-pyrazolo [5,1-b Synthesis of] oxazole-7-sulfofluorenyl) -urea. step 1 To a solution of 1,2-dihydro-pyrazol-3-one (500 mg, 5.9 mmol) in MeCN (50 mL) was added 1,2-dibromo-ethane (3.3 g, 17.6 mmol) and K2 CO3 (2.4 g, 17.6 mmol). After stirring at reflux overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo. By reversed-phase HPLC (H2 MeCN in O, 5% to 95%) purified the residue to give 2,3-dihydro-pyrazolo [5,1-b ] Oxazole (260 mg, 40%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.27 (s, 1H), 5.37 (d,J = 1.6 Hz, 1H), 5.06 (t,J = 8.0 Hz, 2H), 4.23 (t,J = 8.0 Hz, 2H).step 2 Put 2,3-dihydro-pyrazolo [5,1-b ] Oxazole (1 g, 9.1 mmol) dissolved in ClSO3 H (20 mL). After heating at 80 ° C overnight, the reaction mixture was added dropwise to EA (150 mL), NH3 · H2 O (20 mL) and H2 O (150 mL). After stirring at room temperature, the reaction mixture was concentrated in vacuo. The residue was suspended in MeOH (30 mL), stirred for 0.5 h, and the mixture was filtered. The filtrate was evaporated in vacuo and the residue was purified by reverse-phase HPLC (MeCN in water, 0% to 60%) to give 2,3-dihydro-pyrazolo [5,1- as a yellow solidb ] Oxazol-7-sulfonamide (60 mg, 4%).step 3- Manufacturing method E 1,2,3,5,6,7-hexahydro-s- To a solution of dicyclopentadienacene-4-ylamine (55 mg, 0.32 mmol) in THF (10 mL) was added triphosgene (30 mg, 0.1 mmol) and TEA (48 mg, 0.48 mmol). After stirring at room temperature for 2 hr, the reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was then dissolved in THF (5 mL). 2,3-dihydro-pyrazolo [5,1-b ] Oxazol-7-sulfonamide (60 mg, 0.32 mmol) and NaOMe (35 mg, 0.64 mmol). After stirring at room temperature for 3 hr, the reaction was changed from H2 It was quenched with O (10 mL), acidified with 3 N HCl to pH = 3, and extracted with EA (10 mL × 3). Combine the organic phases over anhydrous Na2 SO4 Dry and evaporate in vacuo. The residue was purified by prep-HPLC to give 1-((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl))-3- (2,3-dihydro-pyrazolo [5,1-b ] Oxazole-7-sulfofluorenyl) -urea (6 mg, 5%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.52 (brs, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 6.91 (s, 1H), 5.21 (t,J = 8.0 Hz, 2H), 4.32 (t,J = 8.0 Hz, 2H), 2.78 (t,J = 7.2 Hz, 4H), 2.62 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H). MS: m / z 389.0 (M + H+ ).Examples 20 Shown below (R ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-hydroxy-6,7-di Hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide and (S ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-hydroxy-6,7-di Synthesis of hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 At 0 ℃Racemization - 6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (530 mg, 2.4 mmol) and pyridine (382 mg, 4.8 mmol) in THF (10 mL) was added TBSOTf (702 mg, 2.7 mmol). The reaction was stirred at room temperature for 2 hr. Will be reacted by H2 O (20 mL) was quenched and acidified to pH = 5 with 1 N HCl. By reversed-phase HPLC (MeCN / H2 O) Purify the residue to give 6-((third butyldimethylsilyl) oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 as a white solid , 3] oxazine-3-sulfonamide (330 mg, yield: 41%). MS: m / z 334.1 (M + H+ ).step 2 Resolution by chiral prep-HPLCRacemization - 6-((Third-butyldimethylsilyl) oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (420 mg, 1.3 mmol), resulting in two isomers: as a white solid (S ) -6-((Third-butyldimethylsilyl) oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonate Amidine (180 mg, yield: 42%); white solid (R ) -6-((Third-butyldimethylsilyl) oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonate Phenamine (200 mg, yield: 46%).step 3 to(S ) -6-((Third-butyldimethylsilyl) oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonate To a solution of amidine (180 mg, 0.5 mmol) in THF (4 mL) was added concentrated HCl (4 mL). After stirring at room temperature overnight, the reaction was concentrated under reduced pressure. By reversed-phase HPLC (MeCN / H2 O) Purify the residue to give a white solid (S ) -6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (115 mg, yield: 97%). MS: m / z 220.1 (M + H+ ). (R ) -6-Hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is prepared using the same procedure.step 4 (S) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-hydroxy-6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is as described hereinManufacturing method A Medium synthesis, resulting in the desired product (50 mg, yield: 23%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.66 (d,J = 2.4 Hz, 1H), 4.34 (s, 3H), 4.24 (dd,J = 4.0, 3.2 Hz, 1H), 3.96 (d,J = 12.4 Hz, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H). MS: m / z 419.0 (M + H+ ). (R) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-hydroxy-6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is prepared using the same procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.66 (d,J = 3.2 Hz, 1H), 4.34 (s, 3H), 4.27-4.23 (m, 1H), 3.96 (d,J = 13.6 Hz, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.61 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H). MS: m / z 419.0 (M + H+ ).Examples twenty one Shown belowRacemization - 6- (dimethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6 Synthesis of 7,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 toRacemization - (3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (1.0 g, 3.2 mmol ) To a solution in DCM (5 mL) was added TFA (5 mL) and the mixture was stirred at room temperature for 20 min. The reaction was concentrated to dryness to give a crude yellow solidRacemization - 3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-amine, which was used in the next step without any purification. MS: m / z 218.0 (M + H+ ).step 2 toRacemization - 3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-amine (crude, approx. 3.2 mmol) in MeOH (10 mL) Added HCHO (30%, 3.2 g, 31.5 mmol). The mixture was stirred at room temperature for 2 hr, and then NaBH was added3 CN (2.0 g, 31.5 mmol). The reaction was then stirred at room temperature for 16 hr. By reversed-phase HPLC (0%-95% H2 MeCN) in O), resulting in a white solidRacemization - 3-bromo-N, N-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-amine (410 mg, yield: 53 %).1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s, 1H), 4.45-4.44 (m, 1H), 4.30-4.24 (m, 2H), 4.18-4.11 (m, 1H), 3.00-2.97 (m, 1H), 2.40 (s , 6H). MS: m / z 245.9 (M + H+ ).step 3- Manufacturing method B N at -78 ° C2 Under the atmosphereRacemization - 3-bromo-N, N-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-amine (400 mg, 1.6 mmol) in To a solution in anhydrous THF (5 mL) was slowly added n-BuLi (2.5 M in hexane, 0.7 mL, 1.6 mmol). After stirring for 20 min under cooling, slowly add ZnCl at this temperature2 (1 M in ether, 1.6 mL, 1.6 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 1 hr. TCPC (479 mg, 1.6 mmol) was then added and the mixture was stirred at room temperature for 1 hr. The reaction was partitioned between water (30 mL) and EA (30 mL). The organic layer was washed with brine (30 mL),2 SO4 Dry and concentrate to give a yellow gelatinous crudeRacemization - 6- (dimethylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorobenzene Ester, which was used in the next step without purification.step 4- Manufacturing method C willRacemization - 6- (dimethylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorobenzene Ester (crude, about 1.6 mmol), NH4 A mixture of OH (10 mL) and THF (10 mL) was stirred at 60 ° C overnight. The reaction was concentrated under reduced pressure until 10 mL of liquid remained. The remaining solution was acidified with 1 N HCl to pH = 5. By reversed-phase HPLC (0%-95% H2 MeCN in O) purified residue to give a white solidRacemization - 6- (dimethylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorobenzene Ester (66 mg, yield: 16% over two steps). Alternatively, the solution can be concentrated to dryness and purified by flash chromatography.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.47 (s, 1H), 7.13 (brs, 2H), 4.95-4.41 (m, 2H), 4.23-4.13 (m, 2H), 2.89-2.86 (m, 1H), 2.26 (s, 6H ).step 5- Manufacturing method A toRacemization - 6- (dimethylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorobenzene To a solution of the base ester (66 mg, 0.3 mmol) in THF (5 mL) was added MeONa (18 mg, 0.3 mmol) and the mixture was stirred at room temperature for 20 min, resulting in a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (47 mg, 0.3 mmol) and TEA (55 mg, 0.5 mmol) in THF (5 mL) was added triphosgene (33 mg, 0.1 mmol) in one portion and the mixture was stirred at room temperature under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 20 min. Thereafter, the reaction solution was partitioned between EA (20 mL) and water (20 mL). The aqueous phase was acidified to pH = 5 with 1 N HCl. The formed solid was collected by filtration and dried to give a white solidRacemization - 6- (dimethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6 , 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (27 mg, yield: 22%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.41 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 4.37-4.22 (m, 2H), 4.11-4.09 (m, 1H), 4.03-4.01 (m, 1H ), 2.83-2.82 (m, 1H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.6 Hz, 4H), 2.25 (s, 6H), 1.93-1.86 (m, 4H). MS: m / z 446.0 (M + H+ ).Examples twenty two Shown below (S ) -6- (dimethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide and (R ) -6- (dimethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) Synthesis of -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 Resolution by chiral prep-HPLCRacemization - 6- (dimethylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (110 mg, 0.4 mmol) Obtained as a white solid (S ) -6- (dimethylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (41 mg, yield : 42%) and white solid (R ) -6- (dimethylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (36 mg, yield : 37%).step 2 (S ) -6- (dimethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method A Medium synthesis, resulting in the desired product as a white solid (14 mg, yield: 18%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (brs, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 6.90 (s, 1H), 4.46-4.43 (m, 2H), 4.24-4.12 (m, 2H), 2.92-2.91 (m, 1H), 2.80 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.25 (s, 6H), 1.93-1.90 (m, 4H). MS: m / z 446.0 (M + H+ ). (R ) -6- (dimethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide was synthesized in the same manner, resulting in the product (15 mg, product Rate: 22%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.91 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.54-4.45 (m, 2H), 4.25-4.15 (m, 2H), 2.93-2.91 (m, 1H ), 2.79 (t,J = 7.2 Hz, 4H), 2.62-2.54 (m, 4H), 2.27 (s, 6H), 1.99-1.92 (m, 4H). MS: m / z 446.0 (M + H+ ).Examples twenty three Shown below (R ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide and (S ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6,7 -Synthesis of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 Split by chiral columnRacemization - 6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (460 mg), resulting in two isomers : (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (peak 1, 91 mg) and (S ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (peak 2, 116 mg).step 2 (R ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamideManufacturing method A Synthesized to deliver the desired product as a white solid (44 mg, yield: 31%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (brs, 1H), 7.92 (brs, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.63 (d,J = 11.6 Hz, 1H), 4.36 (d,J = 11.6 Hz, 1H), 4.27-4.19 (m, 2H), 4.06 (s, 1H), 3.34 (overlap, 3H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.93 (m, 4H). MS: m / z 433.0 (M + H+ ). (S ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is prepared using the same procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.51 (s, 1H), 7.98 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.64 (d,J = 11.6 Hz, 1H), 4.37 (d,J = 12.0 Hz, 1H), 4.24-4.22 (m, 2H), 4.05 (s, 1H), 3.34 (overlap, 3H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H). MS: m / z 433.0 (M + H+ ).Examples twenty four Shown below (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfofluorenyl) fluorenamide and (S )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Synthesis of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide sodium. step 1 toRacemization - 6-((tetrahydro-2H-pyran-2-yl) oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (36 g, 0.161 mol) in MeOH (200 mL) and H2 To a solution in O (50 mL) was added concentrated HCl (50 mL). After stirring at room temperature for 1 hr, the reaction solution was concentrated under reduced pressure. The residue was saturated with NaHCO3 Solution (pH = 8) and processed by reversed-phase HPLC (0%-50% H2 MeCN in O), resulting in a yellow solidRacemization - 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (27 g, crude yield: quantitative).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.21 (s, 1H), 5.56 (s, 1H), 5.43 (s, 1H), 4.23-4.15 (m, 4H), 3.94-3.89 (m, 1H).step 2 N at 0 ° C2 DownwardRacemization - NaH was added to a solution of 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (10 g, 71.4 mmol) in anhydrous DMF (150 mL) (60%, 4.3 g, 107 mmol). After stirring at room temperature for 1 hr, MeI (15.2 g, 107 mml) was added to the reaction. The reaction was stirred at room temperature overnight, poured into water (100 mL) and filtered. Dry the cake to give a yellow solidRacemization - 6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (5.5 g, yield: 50%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.21 (s, 1H), 5.44 (s, 1H), 4.44-4.40 (m, 1H), 4.23-4.10 (m, 3H), 3.96 (s, 1H), 3.34 (overlap, 3H).step 3 Split by chiral columnRacemization - 6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (5.5 g) resulting in two isomers: as a white solid (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (peak 1, 2.4 g) and white solid (S ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (peak 2, 2.5 g).step 4 Under ice coolingR ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (2.4 g, 15.6 mmol) was added portionwise to a solution in MeCN NBS (2.78 g, 15.6 mmol). After stirring at room temperature for 1 hr, reversed-phase HPLC (MeCN / H2 O) purifying the reaction solution to produce (R ) -3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (2.6 g, yield: 72%).1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s, 1H), 4.52-4.48 (m, 1H), 4.32-4.20 (m, 3H), 3.93-3.92 (m, 1H), 3.49 (s, 3H). (S ) -3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine was prepared using the same procedure.step 5 (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl ester Department of useManufacturing method B Synthesized to give a yellow oily product which was used in the next step without any purification. (S ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl ester Prepared using the same procedure.step 6 (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method C Medium synthesis, resulting in the desired product as a yellow solid (800 mg, yield: 32% over 2 steps). MS: m / z 234.0 (M + H+ ). (S ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide was prepared using the same procedure.step 7- Manufacturing method D to(R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (800 mg, 3.43 mole) in THF ( 10 mL) was added to MeONa (370 mg, 6.86 mmol). The mixture was stirred at room temperature for 30 min, resulting in a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-amine (891 mg, 5.1 mol) and TEA (1.5 g, 15.3 mmol). ) To the solution in THF (20 mL) was added triphosgene (611 mg, 2.1 mmol) in one portion. N at room temperature2 After stirring for 30 min, the reaction mixture was filtered. The filtrate was added to the above sodium salt suspension and the reaction was stirred at room temperature overnight. Thereafter, the reaction solution was partitioned between EA (50 mL) and water (80 mL). By reversed-phase HPLC (MeCN / H2 O) Purify the aqueous phase to give a yellow solid (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfofluorenyl) fluorenamide sodium (250 mg, yield: 16%).1 H NMR (400 MHz, D2 O): δ = 7.52 (s, 1H), 6.88 (s, 1H), 4.51 (d,J = 12.0 Hz, 1H), 4.16-4.11 (m, 3H), 4.02-4.00 (m, 1H), 3.30 (s, 3H), 2.68 (t,J = 7.2 Hz, 4H), 2.51 (t,J = 7.6 Hz, 4H), 1.90-1.81 (m, 4H). MS: m / z 433.1 (M + H+ ). (S )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium was prepared using the same procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.47 (brs, 1H), δ = 7.39 (s, 1H), 6.78 (s, 1H), 4.49 (dt,J = 8.0 Hz, 2.0 Hz, 1H), 4.23-4.15 (m, 2H), 4.14-4.08 (m, 1H), 3.99-3.95 (m, 1H), 3.34 (s, 3H), 2.75 (t,J = 7.2 Hz, 4H), 2.65 (t,J = 7.2 Hz, 4H), 1.96-1.86 (m, 4H). MS: m / z 433.1 (M + H+ ).Examples 25 Shown below (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Synthesis of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide sodium. step 1 A solution of 1,2-dihydro-pyrazol-3-one (50.0 g, 600 mmol) in pyridine (300 mL) was heated to 95 ° C. To this solution was slowly added a solution of acetic anhydride (61.2 g, 600 mmol) in pyridine (100 mL) over 0.5 hours. The reaction was heated at 95 ° C for another 1 hr. The reaction mixture was concentrated in vacuo to give a dark red oil, which was triturated with MeOH (150 mL) and filtered to give 1-acetamido-1,2-dihydro-pyrazole-3- as a white solid Ketone (54.0 g, yield: 71%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 10.92 (s, 1H), 8.08 (s, 1H), 5.96 (s, 1H), 2.45 (overlap, 3H).step 2 In N2 1-Ethyl-1,2-dihydro-pyrazol-3-one (34.7 g, 280 mol) and PPh3 A mixture of (24.9 g, 420 mol) in THF (400 mL) was cooled to 0 ° C. To the mixture was slowly added DIAD (84.8 g, 420 mmol). The reaction was stirred for an additional hour at 0 ° C and then slowly added (R ) -Ethylene-2-ylmethanol (25.2 g, 340 mmol). The reaction was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by a silica gel column (PE / EA = 10/1) to give a white solid (R ) -1-Ethyl-2- (epoxyethyl-2-ylmethyl) -1H-pyrazole-3 (2H) -one (34.8 g, yield: 68%).1 H NMR (400 MHz, CDCl3 ): δ = 8.06 (d,J = 2.8 Hz, 1H), 6.00 (d,J = 3.2 Hz, 1H), 4.55 (dd,J = 12.0, 3.2 Hz, 1H), 4.20 (dd,J = 12.0, 3.2 Hz, 1H), 3.39 (q,J = 3.2 Hz, 1H), 2.92 (t,J = 4.4 Hz, 1H), 2.76 (dd,J = 4.4, 2.4 Hz, 1H), 2.57 (s, 3H).step 3 At room temperatureR ) -1-Ethyl-2- (epoxyethyl-2-ylmethyl) -1H-pyrazole-3 (2H) -one (34.8 g, 190 mmol) in AcOH (34.2 g, 570 mmol) and To the solution in THF (200 mL) was added LiCl (13.1 g, 310 mmol). The reaction was then stirred at room temperature overnight. The reaction was partitioned between EA (200 mL) and water (200 mL). The organic layer was saturated with NaHCO3 (100 mL) and brine (100 mL), washed with Na2 SO4 Dry and concentrate in vacuo to give a colorless oily crude (R ) -1-Ethyl-2- (3-chloro-2-hydroxypropyl) -1H-pyrazole-3 (2H) -one, which was used in the next step without any purification.1 H NMR (300 MHz, DMSO-d 6 ): δ = 8.25 (d,J = 2.7 Hz, 1H), 6.23 (d,J = 3.0 Hz, 1H), 5.59 (brs, 1H), 4.24-4.19 (m, 2H), 4.07-4.04 (m, 1H), 3.75-3.62 (m, 2H), 2.50 (overlap, 3H). MS: m / z 219.4 (M + H+ ).step 4 will(R ) -1-Ethyl-2- (3-chloro-2-hydroxypropyl) -1H-pyrazole-3 (2H) -one (crude, 190 mmol) and K2 CO3 A mixture of (78.7 g, 570 mmol) in DMF (400 mL) was stirred at 135 ° C overnight. The solvent was removed under reduced pressure. The residue was purified by a silica gel column (EA) to give a white solid (R ) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (12.8 g, yield: 48%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.21 (d,J = 1.6 Hz, 1H), 5.51 (d,J = 3.2 Hz, 1H), 5.44 (d,J = 1.6 Hz, 1H), 4.24-4.13 (m, 4H), 3.92 (d,J = 12.4 Hz, 1H).step 5 N at 0 ° C2 Downward (R ) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (12.8 g, 91.4 mmol) in a solution of MeCN (200 mL), NBS (17.9 g, 100.6 mmol) was added in two portions. The reaction was then stirred at room temperature for 1 hr. The reaction was partitioned between EA (200 mL) and water (200 mL). The organic layer was saturated with NaHCO3 (100 mL) and brine (100 mL), washed with Na2 SO4 Dry and concentrate in vacuo. The residue was triturated with EA (50 mL) and filtered to give a white solid (R ) -3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (11.3 g, yield: 57%). MS: m / z 219.3 (M + H+ ).step 6 to(R ) -3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (12.2 g, 55.7 mmol) in DMF (60 mL) To the solution was added NaH (60% in mineral oil, 2.7 g, 66.8 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. Then MeI (9.5 g, 66.8 mmol) was added. After stirring at room temperature for 2 hr, the reaction was poured into water (200 mL) and extracted with EA (100 mLx2). The organic layer was washed with water (100 mL) and brine (100 mL),2 SO4 Dry and concentrate. Combine the residue with MeOH / H2 O (2/1, 100 mL) was triturated together and filtered to give a white solid (R ) -3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (9.5 g, yield: 73%). MS: m / z 233.3 (M + H+ ).step 7 (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl ester Department of useManufacturing method B Synthesized to give a yellow oily product which was used in the next step without any purification. (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method C Medium synthesis, resulting in the desired product as a white solid (2.6 g, yield: 27% over 2 steps).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.47 (s, 1H), 7.08 (s, 2H), 4.58-4.54 (m, 1H), 4.32-4.18 (m, 3H), 4.01 (d,J = 1.2 Hz, 1H), 3.35 (overlap, 3H).step 8 To 1, 2, 3, 5, 6, 7-hexahydro-s-dicyclopentadienyl-4-ylamine (15.0 g, 87 mmol) and TEA (13.3 mL, 95.4 mmol) at 0 ° C To the solution in THF (30 mL) was added triphosgene (8.5 g, 28.6 mmol) in one portion and the mixture was heated at 70 ° C under N2 Stir for 1 hr. The reaction mixture was then filtered through diatomaceous earth. Wash the filter cake with 30 mL of PE. The filtrate was concentrated to dryness and dissolved in 100 mL of n-hexane. The mixture was filtered through a silicone pad. The filtrate was concentrated to dryness to give 4-isocyano-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene (14.1 g, yield: 81 as a pink oil). %). will(R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (1.6 g, 6.9 mmol) in MeOH ( The suspension in 30 mL) was stirred at 80 ° C until a clear solution was obtained, then MeONa (372.6 mg, 6.9 mmol) was added and the mixture was stirred for 30 min. The solution was concentrated to dryness and the residue was co-evaporated with MeCN (30 mL). The residual solid was suspended in MeCN (30 mL) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-dicyclopentadiene benzene (1.4 g, 7.2 mmol) was added ). The mixture solution was stirred at room temperature for 16 hr and filtered. Mill the filter cake with PE / EA (5/1, 40 mL) to give a white solid (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) fluorenamide sodium (2.4 g, yield: 80%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 4.50 (d,J = 12.0 Hz, 1H), 4.21-4.08 (m, 3H), 3.95 (s, 1H), 3.34 (overlap, 3H), 2.76 (t,J = 6.8 Hz, 4H), 2.67 (t,J = 6.8 Hz, 4H), 1.94-1.88 (m, 4H). MS: m / z 433.1 (M + H+ ).Examples 26 Shown below (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Synthesis of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide sodium. step 1 At 0 ° CR ) -3-chloropropane-1,2-diol (61.0 g, 552.0 mmol) in pyridine (450 mL) was added portionwise with TsCl (105.2 g, 552.0 mmol). After stirring at room temperature for 1 hr, the reaction was treated with H2 O (10 mL) was quenched and concentrated. The residue was poured into aq. HCl (2 N, 200 mL) and extracted with DCM (300 mL x 3). Combine the combined organic layers with saturated NaHCO3 (300 mL) washed with Na2 SO4 Dried and concentrated to give a yellow oil (R ) -4-toluenesulfonic acid 3-chloro-2-hydroxypropyl ester (121.8 g, crude, yield: 76%).step 2 will(R ) -4-toluenesulfonic acid 3-chloro-2-hydroxypropyl ester (121.8 g, 461.4 mmol), CH3 I (43 mL, 690.4 mmol) and Ag2 A mixture of O (128.0 g, 551.7 mmol) in DCM (1 L) was refluxed at 45 ° C for 24 hr. Add another CH3 I (28.7 mL, 460.8 mmol) and the reaction was refluxed for another 24 hr. Remove Ag by filtration2 O and the filtrate was concentrated and purified by a silica gel column (PE / EA = 8/1) to give a yellow oil (R ) -4-toluenesulfonic acid 3-chloro-2-methoxypropyl ester (77.0 g, yield: 60%).1 H NMR (300 MHz, CDCl3 ): δ = 7.79 (d,J = 8.1 Hz, 2H), 7.35 (d,J = 8.1 Hz, 2H), 4.15-4.08 (m, 2H), 3.64-3.50 (m, 3H), 3.38 (s, 3H), 2.44 (s, 3H).step 3 ~ 4 will(R ) -4-toluenesulfonic acid 3-chloro-2-methoxypropyl ester (26.2 g, 94.2 mmol), 1-ethylfluorenyl-1,2-dihydro-pyrazol-3-one (11.9 g, 94.2 mmol) and K2 CO3 A mixture of (39.0 g, 282.6 mmol) in DMF (350 mL) was stirred at 50 ° C for 16 hr. Add H2 O (35 mL) and the reaction was stirred at 130 ° C for another 3 hr. Remove K by filtering2 CO3 And the filtrate was concentrated. The residue was purified by a silica gel column (PE / EA = 2/1) to give a white solid (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (13.8 g, containing some DMF and unknown by-products, yield: 95 %).1 H NMR (400 MHz, CDCl3 ): δ = 7.33 (d,J = 2.0 Hz, 1H), 5.50 (d,J = 2.4 Hz, 1H), 4.40-4.34 (m, 1H), 4.32-4.23 (m, 2H), 4.17 (dd,J = 11.6, 1.6 Hz, 1H), 3.92-3.89 (m, 1H), 3.48 (s, 3H).step 5 At 0 ° CR ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (13.8 g, 89.6 mmol) in DCM (150 mL) ClSO3 H (13.1 mL, 197.1 mmol). After stirring at room temperature for 16 hr, pyridine (15.8 mL, 197.1 mmol) was added dropwise at 0 ° C and then PCl was added portionwise at 0 ° C.5 (41.0 g, 197.1 mmol). The reaction mixture was stirred at room temperature for 1 hr, poured onto ice water (200 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL),2 SO4 Dried and concentrated to give a yellow solid (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride (16.7 g, crude, yield: 74 %).step 6 to(R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride (16.7 g, 66.3 mmol) in THF ( 100 mL)3 .H2 O (42 mL). After stirring at 60 ° C for 2 hr, the reaction mixture was concentrated to about 20 mL. The residual suspension was acidified with aq. HCl (1 N) to pH = 3 and filtered. Filter cake with H2 O (50 mL) was washed and triturated with MeOH (20 mL) to give a white solid (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (10.7 g, yield: 69%) .1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.49 (s, 1H), 7.12 (s, 2H), 4.59 (td,J = 11.6, 2.4 Hz, 1H), 4.32 (d,J = 12.0 Hz, 1H), 4.27-4.17 (m, 2H), 4.04-4.02 (m, 1H), 3.35 (s, 3H).step 7 (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-methoxy-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfofluorenyl) fluorene is as in the previous examplestep 8 Synthesized as described above to give the desired product as a white solid (2.4 g, yield: 80%).Examples 27 Shown below (R ) -6-Methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 N at -78 ° C2 Downward (R ) -3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (1.0 g, 4.3 mmol) in anhydrous THF (10 mL To the solution in), n-BuLi (2.5 M, 2.1 mL, 5.2 mmol) in hexane was slowly added. After stirring for 1 hr under cooling, slowly add (BnS) at this temperature2 (1.6 g, 6.5 mmol). The cooling bath was removed and the reaction was stirred at room temperature overnight. Saturate the reaction with saturated NH4 The Cl solution (5 mL) was quenched and partitioned between water (20 mL) and EA (20 mL). The organic layer was washed with brine (20 mL) and2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give a yellow oil (R ) -3- (benzylthio) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (760 mg, yield: 63%). MS: m / z 277.4 (M + H+ ).step 2 N at 0 ° C2 Downward (R ) -3- (benzylthio) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (750 mg, 2.7 mmol) At AcOH / H2 To a solution in O (3 mL / 1 mL), add NCS (1.5 g, 10.9 mmol) in two portions. The reaction was then stirred at room temperature for 1 hr. The reaction was partitioned between EA (20 mL) and water (20 mL). The organic layer was saturated with NaHCO3 (20 mL) and brine (20 mL), washed with Na2 SO4 Dry and concentrate in vacuo to give a yellow oily crude (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride, which was used without any purification One step.step 3 (R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method C Medium synthesis, resulting in the desired product as a white solid (280 mg, yield: 44% over 2 steps).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.48 (s, 1H), 7.11 (s, 2H), 4.61-4.56 (m, 1H), 4.34 (d,J = 11.6 Hz, 1H), 4.26-4.16 (m, 2H), 4.03 (d,J = 1.2 Hz, 1H), 3.35 (s, 3H). MS: m / z 233.8 (M + H+ ).Examples 28 Shown belowRacemization - N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methyl-6,7-dihydro Synthesis of -5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 In N2 To a solution of 2-methyl-propane-1,3-diol (1 g, 11.1 mmol) and TEA (4.5 g, 44.4 mmol) in THF (30 mL) under ice cooling was slowly added MsCl (2.8 g, 24.4 mmol). The reaction was stirred at room temperature for 1 hr and filtered. The filtrate was concentrated to give a colorless oil. This oil is 1,2-dihydro-pyrazol-3-one (993 mg, 11.1 mmol) and K2 CO3 A mixture of (6.1 g, 44.4 mmol) in DMF (40 mL) was heated to 80 ° C and held for 12 hr. The reaction was cooled and partitioned between EA (100 mL) and water (200 mL) and the layers were separated. The organic layer was washed with water (80 mL) and brine (50 mL).2 SO4 Dry and concentrate. Purification of the residue by a silica gel column (PE / EA = 2/1) gave a white solidRacemization - 6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (500 mg, yield: 33%).1 H NMR (300 MHz, CDCl3 ): δ = 7.31 (s, 1H), 5.47 (s, 1H), 4.27-4.23 (m, 2H), 3.87-3.68 (m, 2H), 2.47-2.45 (m, 1H), 1.23-1.09 (m , 3H). MS: m / z 139.0 (M + H+ ).step 2 ~ 3 willRacemization - A solution of 6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (500 mg, 3.6 mmol) in chlorosulfonic acid (5 mL) Stir overnight at 80 ° C. The reaction was dissolved in EA (60 mL) and slowly added to water (100 mL). The organic layer was washed with brine (60 mL),2 SO4 Dry and concentrate. The residue was dissolved in THF (15 mL) and ammonia (5 mL) was added. The mixture was stirred at 60 ° C for 1 hr. The reaction was concentrated, acidified with 1 N HCl and reversed-phase HPLC (MeCN / H2 O) Purified to give a white solidRacemization - 6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (450 mg, yield: 58 in 2 steps) %).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.46 (s, 1H), 7.11 (brs, 2H), 4.43-4.38 (m, 1H), 4.21-4.15 (m, 1H), 4.06-3.99 (m, 1H), 3.76-3.69 (m , 1H), 2.42-2.34 (m, 1H), 1.02-1.00 (m, 3H).step 4 Racemization - N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methyl-6,7-dihydro -5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamideManufacturing method A Synthesized to deliver the desired product as a white solid (29.7 mg, yield: 18%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.49 (s, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.48-4.45 (m, 1H), 4.44-4.18 (m, 1H), 4.08 (t,J = 11.4 Hz, 1H), 3.77-3.72 (m, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 2.40 (overlapping, 1H), 1.98-1.91 (m, 4H), 1.01 (d,J = 6.4 Hz, 3H). MS: m / z 417.0 (M + H+ ).Examples 29 Shown below (S ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methyl-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide and (R ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methyl-6,7- Synthesis of Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 Resolution by chiral prep-HPLCRacemization - 6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (350 mg), which produces (S ) -6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (242 mg, as diethylamine salt) and(R ) -6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (240 mg, as diethylamine salt) .step 2 (R ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methyl-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method A Medium synthesis, resulting in the desired product (112 mg, yield: 37%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (brs, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.48-4.45 (m, 1H), 4.44-4.18 (m, 1H), 4.08 (t,J = 11.4 Hz, 1H), 3.77-3.72 (m, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 2.40 (overlapping, 1H), 1.98-1.91 (m, 4H), 1.00 (d,J = 6.4 Hz, 3H). MS: m / z 417.1 (M + H+ ). (S ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methyl-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide was prepared using the same procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.48-4.44 (m, 1H), 4.22-4.18 (m, 1H), 4.11-4.06 (m, 1H), 3.77-3.72 (m, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.42-2.38 (m, 1H), 1.98-1.92 (m, 4H), 1.00 (d,J = 6.8 Hz, 3H). MS: m / z 417.1 (M + H+ ).Examples 30 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -5 ', 7'-dihydrospiro Synthesis of [cyclopropane-1,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'-sulfamethoxamine. step 1 In N2 To a solution of (1-hydroxymethyl-cyclopropyl) -methanol (1.53 g, 15 mmol) and TEA (6.1 g, 60 mmol) in THF (45 mL) under ice cooling was slowly added MsCl (3.8 g, 33 mmol). After stirring for 1 hr at room temperature, the reaction was partitioned between EA (500 mL) and water (100 mL). The organic layer was washed with brine (100 mL),2 SO4 Dry and concentrate to give a colorless oil. This oil is 1,2-dihydro-pyrazol-3-one (1.3 g, 15 mmol) and K2 CO3 A mixture of (8.3 g, 60 mmol) in DMF (60 mL) was heated to 80 ° C overnight. The reaction was cooled and partitioned between EA (120 mL) and water (300 mL). The organic layer was washed with water (100 mL) and brine (80 mL).2 SO4 Dry and concentrate. By reversed-phase HPLC (MeCN / H2 O) Purify the residue to give 5 ', 7'-dihydrospiro [cyclopropane-1,6'-pyrazolo [5,1-b] [1,3] oxazine] (380 mg as a white solid) , Yield: 17%).1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (d,J = 1.8 Hz, 1H), 5.52 (d,J = 1.8 Hz, 1H), 3.99 (s, 4H), 0.81-0.49 (m, 4H). MS: m / z 151.0 (M + H+ ).step 2 5 ', 7'-Dihydrospiro [cyclopropane-1,6'-pyrazolo [5,1-b] [1,3] oxazine] (380 mg, 5.3 mmol) in MeCN (15 mL) To the solution was added NBS (960 mg, 5 mmol) in portions. After stirring for 1 hr at room temperature, the reaction was partitioned between EA (60 mL) and water (60 mL). The organic layer was washed with brine (60 mL),2 SO4 Dry and concentrate. The residue was purified by silica gel column (PE / EA = 2/1) to a yellow solid 3'-bromo-5 ', 7'-dihydrospiro [cyclopropane-1,6'-pyrazolo [5 , 1-b] [1,3] oxazine] (380 mg, yield: 66%).1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s, 1H), 4.07 (s, 2H), 3.98 (s, 2H), 0.86-0.81 (m, 4H). MS: m / z 230.9 (M + H+ ).step 3 5 ', 7'-Dihydrospiro [cyclopropane-1,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'-sulfonic acid 2,4,6-trichloro Use of phenyl esterManufacturing method B Synthesized to give a yellow oily product which was used in the next step without any purification.step 4 5 ', 7'-dihydrospiro [cyclopropane-1,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'-sulfonamideManufacturing method C Medium synthesis, resulting in the desired product as a white solid (105 mg, yield: 27% over 2 steps).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.49 (s, 1H), 7.12 (brs, 2H), 4.20 (s, 2H), 4.00 (s, 2H), 0.78 (s, 4H).step 5 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -5 ', 7'-dihydrospiro [ring Propane-1,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'-sulfonamideManufacturing method A Synthesized to deliver the desired product as a white solid (54 mg, yield: 34%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.53 (s, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 6.94 (s, 1H), 4.25 (s, 2H), 4.01 (s, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.93 (m, 4H), 0.78 (s, 4H). MS: m / z 429.0 (M + H+ ).Examples 31 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amidomethyl) -1-toluenesulfonyl-5 ' Synthesis of 7,7'-dihydrospiro [azetidin-3,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'-sulfonamide. step 1 To [3-bromomethyl-1- (toluene-4-sulfonyl) -azetidin-3-yl] -methanol (4 g, 12 mmol) in DCM (60 mL) at 0 ° C. CBr added to the solution4 (6.4 g, 19.2 mmol) and PPh3 (5.2 g, 19.2 mmol). After stirring for 16 hr at room temperature, the reaction was partitioned between DCM (200 mL) and H2 O (200 mL). The aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with brine (100 mL),2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 5/1) to give 3,3-bis-bromomethyl-1- (toluene-4-sulfonyl) -azetidine as a yellow solid. (3.8 g, yield: 79%). MS: m / z 395.9 (M + H+ ).step 2 To 3,3-bis-bromomethyl-1- (toluene-4-sulfonyl) -azetidine (4.2 g, 10.6 mmol) and 1,2-dihydro-pyrazol-3-one 0.89 g, 10.6 mmol) in DMF (50 mL)2 CO3 (3.7 g, 26.5 mmol). After stirring at 130 ° C for 16 hr, the reaction was cooled and quenched with the addition of EA (100 mL) and water (100 mL). The organic layer was separated. The aqueous layer was extracted with EA (100 mL). The organic layers were combined, washed with brine (80 mL),2 SO4 Dry and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 1/1) to give 1-tosylsulfonyl-5 ', 7'-dihydrospiro [azetidine-3,6' as a white solid -Pyrazolo [5,1-b] [1,3] oxazine] (1.4 g, yield: 42%). MS: m / z 320 (M + H+ ).step 3 To 1-toluenesulfonyl-5 ', 7'-dihydrospiro [azetidin-3,6'-pyrazolo [5,1-b] [1,3] oxazine at 0 ° C ] (1 g, 0.33 mmol) in a solution in MeCN (10 mL) was added NBS (0.64 g, 3.6 mmol) in portions and the reaction was stirred at room temperature for 2 hr. Filter the mixture and reverse-phase HPLC (5%-95% H2 MeCN in O) purified the filtrate to yield 3'-bromo-1-tosylsulfonyl-5 ', 7'-dihydrospiro [azetidine-3,6'-pyrazolo [ 5,1-b] [1,3] oxazine] (1.16 g, yield: 83%). MS: m / z 398 (M + H+ ).step 4 1-toluenesulfonyl-5 ', 7'-dihydrospiro [azetidin-3,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'- 2,4,6-trichlorophenyl sulfonateManufacturing method B Synthesized to give a yellow oily product. 1-toluenesulfonyl-5 ', 7'-dihydrospiro [azetidin-3,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'- SulfonamideManufacturing method C Medium synthesis, resulting in the desired product (140 mg, yield: 32%) as a pale yellow solid. MS: m / z 399.1 (M + H+ ).step 5 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -1-toluenesulfonyl-5 ', 7 '-Dihydrospiro [azetidin-3,6'-pyrazolo [5,1-b] [1,3] oxazine] -3'-sulfonamideManufacturing method A Synthesized and further purified by prep HPLC to deliver the desired product as a white solid (24 mg, yield: 22%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.52 (s, 1H), 7.90 (s, 1H), 7.74 (d,J = 8.0 Hz, 2H), 7.62 (s, 1H), 7.53 (d,J = 8.0 Hz, 2H), 6.94 (s, 1H), 4.24 (s, 2H), 4.00 (s, 2H), 3.68 (s, 4H), 2.80 (t,J = 7.2 Hz, 4H), 2.55 (t,J = 6.8 Hz, 4H), 2.46 (s, 3H), 1.91-1.98 (m, 4H). MS: m / z 598.2 (M + H+ ).Examples 32 The following shows 6-amino-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7- Synthesis of Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 To a solution of 2-aminopropane-1,3-diol (5.0 g, 54.9 mmol) and TEA (11.1 g, 109.9 mmol) in DCM (40 mL) was added Boc2 O (14.4 g, 65.9 mmol) and the reaction was stirred at room temperature for 2 hr. The reaction was partitioned between water (80 mL) and EA (80 mL). The organic layer was washed with brine (80 mL),2 SO4 Dry and concentrate to give the crude (1,3-dihydroxyprop-2-yl) carbamic acid third butyl ester as a white solid, which was used in the next step without any purification.step 2 To (1,3-dihydroxyprop-2-yl) aminocarboxylic acid third butyl ester (crude, about 21.0 mmol) and TEA (8.5 g, 84.0 mmol) in anhydrous THF (30 mL) at 0 ° C To this solution was added MsCl (5.3 g, 46.0 mmol). After stirring at room temperature for 2 hr, the reaction was filtered. The filtrate was concentrated to dryness. The residue was purified by a silica gel column (PE / EA = 1/1) to give 2-((third butoxycarbonyl) amino) propane-1,3-diyl dimethanesulfonate as a white solid. (3.9 g, yield: 53%).1 H NMR (300 MHz, CDCl3 ): δ = 5.11 (d,J = 7.5 Hz, 1H), 4.36-4.22 (m, 5H), 3.07 (s, 6H), 1.44 (s, 9H).step 3 Dimethanesulfonic acid 2-((third butoxycarbonyl) amino) propane-1,3-diyl ester (3.9 g, 11.2 mmol), 1,2-dihydro-pyrazol-3-one ( 945 mg, 11.2 mmol) and K2 CO3 A mixture of (5.4 g, 39.3 mmol) in DMF (30 mL) was heated to 80 ° C and held for 12 hr. The reaction was cooled and partitioned between EA (150 mL) and water (200 mL). The organic layer was washed with water (80 mL) and brine (50 mL).2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give (6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine as a white solid -6-yl) tributylcarbamate (975 mg, yield: 13%).1 H NMR (300 MHz, CDCl3 ): δ = 7.37 (d,J = 1.2 Hz, 1H), 5.55 (d,J = 1.5 Hz, 1H), 5.14-5.04 (m, 1H), 4.43-4.12 (m, 5H), 1.46 (s, 9H). MS: m / z 240.1 (M + H+ ).step 4 N at 0 ° C2 (6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) carbamic acid third butyl ester (610 mg, 2.6 mmol) In a solution in MeCN, add NBS (454 mg, 2.6 mmol) in two portions. The reaction was then stirred at room temperature for 1 hr. The reaction was partitioned between EA (20 mL) and water (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL).2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give a white solid (3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Triazine-6-yl) aminocarbamic acid third butyl ester (640 mg, yield: 79%). MS: m / z 318.0 (M + H+ ).step 5 6-((third butoxycarbonyl) amino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4, 6-trichlorophenyl esterManufacturing method B Synthesis, resulting in a yellow gel-like product, which was used in the next step without any purification.step 6 6-((Third-butoxycarbonyl) amino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4 , 6-trichlorophenyl ester (crude, about 1.9 mmol), NH4 The mixture in OH (20 mL) and THF (20 mL) was stirred at 60 ° C overnight. The reaction was concentrated under reduced pressure until 10 mL of liquid remained. The remaining solution was acidified with 1 N HCl to pH = 5 and extracted with EA (20 mL x 2). Combine the organic layers over Na2 SO4 Dry and concentrate. The residue was purified by a silica gel column (DCM / MeOH = 40/1) to give a yellow semi-solid (3-aminesulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] oxazin-6-yl) tributylcarbamate (80 mg, yield: 13% over 2 steps). MS: m / z 317.0 (M-H+ ).step 7 (3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylfluorenyl) aminesulfonyl) -6, 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl esterManufacturing method A Synthesized to deliver the desired product as a white solid (28 mg, yield: 22%).step 8 To (3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylsulfanyl) aminesulfonyl) -6 , 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (28 mg, 0.05 mmol) in DCM (5 mL To the solution in) was added TFA (5 mL) and the mixture was stirred at room temperature for 20 min. The reaction was concentrated to dryness and the residue was triturated with EA to give 6-amino-N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentane) as a white solid Enacene-4-yl) carboxamidinyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide TFA salt ( 5.4 mg, yield: 23%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.15 (brs, 1H), 7.54 (s, 1H), 6.88 (s, 1H), 4.32-4.30 (m, 1H), 4.21-4.16 (m, 1H), 4.11-4.01 (m, 1H ), 3.81-3.75 (m, 1H), 3.47 (overlapping, 1H), 2.77 (t,J = 7.2 Hz, 4H), 2.67-2.62 (m, 4H), 1.97-1.92 (m, 4H). MS: m / z 418.2 (M + H+ ).Examples 33 The following shows ((6-(((third-butoxycarbonyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- Synthesis of 3-yl) sulfofluorenyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamidino) phosphonium sodium. step 1 Add 1,2-dihydro-pyrazol-3-one (10.42 g, 0.124 mol) and K2 CO3 (42.8 g, 0.31 mol) in DMF (700 mL) was heated to 100 ° C. 3-Chloro-2-chloromethyl-propylene (15.5 g, 0.124 mol) was added and the mixture was stirred at 100 ° C for 16 hr. Remove the solvent in vacuo. Partition the residue between EA (200 mL) and H2 O (500 mL). The aqueous layer was extracted with EA (200 mL). The combined organic layers were washed with brine (100 mL),2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give 6-methylene-6,7-dihydro-5H-pyrazolo [5,1-b] [1 as a yellow oil , 3] oxazine (1.7 g, yield: 10%).1 H NMR (300 MHz, CDCl3 ): δ = 7.34 (s, 1H), 5.51 (s, 1H), 5.39 (s, 2H), 4.80 (s, 2H), 4.63 (s, 2H). MS: m / z 137.1 (M + H+ ).step 2 To 6-methylene-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (1.7 g, 12.5 mmol) in THF (20 mL) at 0 ° C BH3 / Me2 S (10 M, 5 mL, 50 mmol). After stirring at room temperature for 16 hr, NaOH solution (3 M, 50 mL, 150 mmol) and H were slowly added to the reaction.2 O2 (30%, 5.7 g, 50 mmol). After stirring at 80 ° C for 2 hr, the reaction was cooled. Add saturated Na to the reaction2 SO3 Aqueous solution (50 mL). After stirring at room temperature for 0.5 hr, the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL),2 SO4 Dry and concentrate to give (6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) -methanol (1.3 g, yield: 68%).1 H NMR (300 MHz, CDCl3 ): δ = 7.31 (d,J = 1.8 Hz, 1H), 5.49 (d,J = 1.8 Hz, 1H), 4.37 (dd,J = 11.4, 3 Hz, 1H), 4.28-4.12 (m, 2H), 4.07-4.00 (m, 1H), 3.77 (d,J = 6.6 Hz, 2H), 2.58-2.50 (m, 1H).step 3 (6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) -methanol (2.05 g, 13.3 mmol) in THF (30 To the solution in mL) was added DPPA (7.3 g, 26.6 mmol) and DBU (6.1 g, 39.9 mmol). The suspension was stirred at 60 ° C for 16 hr. The reaction was quenched with the addition of EA (100 mL) and water (100 mL). The organic layer was separated. The aqueous layer was extracted with EA (100 mL). The organic layer was washed with brine (100 mL),2 SO4 Dry and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 2/1) to produce 6-azidomethyl-6,7-dihydro-5H-pyrazolo [5,1-b] as a yellow oil. [1,3] oxazine (1.24 g, yield: 62%). MS: m / z 180.3 (M + H+ ).step 4 To 6-azidomethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (1.24 g, 16.9 mmol) in MeOH (20 mL) Add Boc to the solution2 O (3 g, 13.8 mmol) and Pd / C (5%, 0.2 g). Place the mixture in H2 (Balloon atmosphere) stirred at room temperature for 16 hr. The reaction was filtered and the filtrate was concentrated to give the crude product, which was used directly in the next step without further purification. MS: m / z 254.0 (M + H+ ).step 5 To ((6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) carbamic acid third butyl ester at 0 ° C ( A solution of crude, 6.9 mmol) in MeCN (20 mL) was added with NBS (1.3 g, 24.7 mmol) in portions and the reaction was stirred at room temperature for 2 hr. The mixture was filtered and passed through reversed-phase HPLC (5%-95% H2 MeCN in O) was purified to give ((3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl Tris (butyl) aminoformate (1.62 g, yield: 71%). MS: m / z 331.9 (M + H+ ).step 6 6-(((third-butoxycarbonyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl esterManufacturing method B Synthesized to give a yellow oily product which was used in the next step without any purification.step 7 ((3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) aminocarboxylic acid tert-butyl Esters such asManufacturing method C Medium synthesis, resulting in the desired product as a pale yellow solid (80 mg, yield: 33% over 2 steps). MS: m / z 333.4 (M + H+ ).step 8 ((6-(((third-butoxycarbonyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3- (Sulfo) sulfonyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethane)Manufacturing method D Medium synthesis, resulting in the desired product as a white solid (27 mg, yield: 21%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.35 (s, 1H), 7.31 (s, 1H), 7.11 (s, 1H), 6.75 (s, 1H), 4.31 (d,J = 5.6 Hz, 1H), 4.10-3.98 (m, 2H), 3.78 (dd,J = 10.0, 2.0 Hz, 1H), 3.07-3.04 (m, 2H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.40-2.3 (m, 1H), 1.93-1.86 (m, 4H), 1.39 (s, 9H). MS: m / z 532.2 (M + H+ ).Examples 34 Shown belowRacemization - N-((3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamido) aminesulfonyl) Synthesis of -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) acetamidin. step 1 toRacemization - ((6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) amino butyl formate (crude, about 1.05 mmol ) To a solution in DCM (3 mL) was added TFA (1 mL). After the solution was stirred at room temperature for 2 hr, the solution was concentrated and treated with Ac2 O (3 mL) was dissolved. After stirring at reflux for 3 hr, the reaction solution was quenched with the addition of EA (20 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with EA (10 mL). The organic layers were combined and washed with brine (10 mL) and2 SO4 dry. The solution was concentrated in vacuo. Purification of the residue by a silica gel column (PE / EA = 1/1) gave a yellow oilRacemization - N-Acetyl-N-((6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) acetamidine (90 mg , Yield: 31%). MS: m / z 238.4 (M + H+ ).step 2 At 0 ℃Racemization - N-Acetyl-N-((6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) acetamidine (90 mg , 0.38 mmol) in DCM (2 mL)3 H (0.075 mL, 1.14 mmol). After stirring at room temperature for 16 hr, pyridine (0.092 mL, 1.14 mmol) was added dropwise to the reaction at 0 ° C, and then PCl was added portionwise.5 (237 mg, 1.14 mmol). The reaction mixture was stirred at room temperature for 1 hr, poured into ice water (2 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL),2 SO4 Dry and concentrate to give the crude product, which was used directly in the next step without further purification.step 3 toRacemization - 6-((N-Ethylacetamido) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride (Crude, ca. 0.387 mmol) in THF (3 mL) was added NH3 .H2 O (3 mL). After stirring at 60 ° C for 2 hr, the reaction mixture was concentrated to about 1 mL. The residual suspension was acidified with aq. HCl (1 N) to pH = 3 and filtered. By reversed-phase HPLC (MeCN / H2 O) Purify the filtrate to give a white solidRacemization - N-((3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) acetamidine (67 mg, yield: 64%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.02 (brs, 1H), 7.37 (s, 1H), 6.65 (brs, 2H), 4.40-4.30 (m, 1H), 4.17-4.04 (m, 2H), 3.85-3.73 (m, 1H ), 3.10-3.00 (m, 2H), 2.50 (overlapping, 1H), 1.76 (s, 3H).step 4 Racemization - N-((3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamido) aminesulfonyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) acetamidoManufacturing method D Medium synthesis, resulting in the desired product as a white solid (34 mg, yield: 48%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (s, 1H), 8.07 (t,J = 6 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.48 (d,J = 8.8 Hz, 1H), 4.26-4.14 (m, 2H), 3.93-3.85 (m, 1H), 3.23-3.08 (m, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.59 (t,J = 6.8 Hz, 4H), 2.50 (overlapping, 1H), 2.10-1.90 (m, 4H), 1.83 (s, 3H). MS: m / z 474.2 (M + H+ ).Examples 35 Shown belowRacemization - 6-((dimethylamino) methyl) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amine formamidine Synthesis of 6), 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 At 0 ℃Racemization - ((3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) aminocarboxylic acid tert-butyl To a solution of the ester (110 mg, 0.33 mmol) in MeOH (2 mL) was added HCl / dioxane (4 M, 1 mL, 4 mmol). After stirring at room temperature for 2 hr, the solution was concentrated to give a crudeRacemization - 6- (aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamido hydrochloride, which was used without further purification That is used directly in the next step.step 2 toRacemization - 6- (aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide hydrochloride (crude, 0.33 mmol) Add HCHO (1.5 mL) and NaCNBH to the solution in MeOH (2 mL)3 (20.8 mg, 0.33 mmol). After stirring at room temperature for 3 hr, the reaction was filtered and reversed-phase HPLC (MeCN / H2 O) Purify the filtrate to give a white solidRacemization - 6-((dimethylamino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (50 mg, Yield: 59%). MS: m / z 261.1 (M + H+ ).step 3 Racemization - 6-((dimethylamino) methyl) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amine formamidine ) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamideManufacturing method D Medium synthesis, resulting in the desired product as a white solid (27 mg, yield: 21%).1 H NMR (400 MHz, DMSO-d 6 + CD3 OD): δ = 7.37 (s, 1H), 7.32 (s, 1H), 6.75 (s, 1H), 4.37 (dd,J = 6.8, 2.8 Hz, 1H), 4.10-4.00 (m, 2H), 3.80-3.75 (m, 1H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.47-2.43 (m, 1H), 2.23 (d,J = 7.2 Hz, 2H), 2.14 (s, 6H), 1.95-1.85 (m, 4H). MS: m / z 460.1 (M + H+ ).Examples 36 Shown belowRacemization - N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6- (methoxymethyl) -6 Synthesis of 7,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 At 0 ℃Racemization - (6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) -methanol (0.6 g, 3.9 mmol) in THF (10 mL) To this was added NaH (187 mg, 4.7 mmol), followed by MeI (667 mg, 4.7 mmol). After stirring overnight, the reaction was quenched with the addition of EA (20 mL) and water (20 mL). The organic layer was separated. The aqueous layer was extracted with EA (20 mL). The organic layers were combined, washed with brine (30 mL),2 SO4 Dry and concentrate in vacuo. Purification of the residue by a silica gel column (PE / EA = 1/1) gave a yellow solidRacemization - 6-methoxymethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (270 mg, yield: 41%). MS: m / z 169.3 (M + H+ ).step 2 Add 6-methoxymethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (230 mg, 1.37 mmol) to MeCN (5 To the solution in mL) was added NBS (256 mg, 1.44 mmol) in portions and the reaction was stirred at room temperature for 2 hr. Filter the mixture and reverse-phase HPLC (5%-95% H2 MeCN in O) purified the filtrate to give 3-bromo-6- (methoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 as a yellow oil ] Oxazine (220 mg, yield: 65%). MS: m / z 247.3 (M + H+ ).step 3 6- (methoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorobenzene Base esterManufacturing method B Synthesized to give a yellow oily product which was used in the next step without any purification.step 4 6- (methoxymethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method C Medium synthesis, resulting in the desired product as a pale yellow solid (25 mg, yield: 13% over 2 steps).step 5 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6- (methoxymethyl) -6 , 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method D Medium synthesis, resulting in the desired product as a white solid (9 mg, yield: 20%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.46 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.51 (dd,J = 10.8, 2.8 Hz, 1H), 4.29 (dd,J = 11.2, 7.2 Hz, 1H), 4.51 (dd,J = 12.4, 5.2 Hz, 1H), 4.51 (dd,J = 12.4, 7.2 Hz, 1H), 3.43 (d,J = 3.6 Hz, 2H), 3.25 (s, 3H), 2.79 (t,J = 7.2 Hz, 4H), 2.61-2.58 (m, 5H), 1.99-1.92 (m, 4H). MS: m / z 446.8 (M + H+ ).Examples 37 Shown belowRacemization - 6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di Synthesis of hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 toRacemization - 3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (700 mg, 3.2 mmol) in DMF (10 mL) Add NaH (60% in mineral oil, 192 mg, 4.8 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. Then iodoethane (549 mg, 3.5 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (60 mL) and extracted with EA (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL).2 SO4 Dry and concentrate. By reversed-phase HPLC (MeCN / H2 O) Purification of the residue to give a white solidRacemization - 3-bromo-6-ethoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (640 mg, yield: 81%). MS: m / z 248.9 (M + H+ ).step 2 6-ethoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl esterManufacturing method B Synthesized to give a yellow oily product which was used in the next step without any purification.step 3 willRacemization - 6-ethoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl ester (crude ) And NH3 .H2 A solution of O (8.4 mL) in THF (8.4 mL) was stirred at 60 ° C for 16 hr. The mixture was concentrated in vacuo. By reversed-phase HPLC (MeCN / H2 O) Purification of the residue to give a white solidRacemization - 6-ethoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (222.0 mg, yield: 35%). MS: m / z 247.9 (M + H+ ).step 4- Manufacturing method F toRacemization - 6-ethoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (116 mg, 0.47 mmol) in THF (8.0 mL MeONa (28 mg, 0.52 mmol) was added to the solution in) and the mixture was stirred at room temperature for 20 min, resulting in a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (81 mg, 0.47 mmol) and TEA (142 mg, 1.4 To the solution in THF (10 mL) was added triphosgene (56.0 mg, 0.19 mmol) in one portion and the mixture was stirred at room temperature under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and the mixture was stirred at room temperature for 20 min. Thereafter, the reaction solution was partitioned between EA (60 mL) and water (60 mL). The aqueous phase was acidified with concentrated HCl to pH = 5 and extracted with EA (60 mL). The organic layer was washed with water (50 mL) and brine (50 mL).2 SO4 Dry and concentrate until a white solid appears. The formed solid was collected by filtration and dried to give a white solidRacemization - 6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di Hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (68 mg, yield: 32%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.58 (d,J = 11.6 Hz, 1H), 4.36 (d,J = 11.6 Hz, 1H), 4.27-4.24 (m, 1H), 4.18-4.15 (m, 2H), 3.61-3.56 (m, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.91 (m, 4H), 1.09 (t,J = 7.2 Hz, 3H). MS: m / z 447.0 (M + H+ ).Examples 38 Shown below (R ) -6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide and (S ) -6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7 -Synthesis of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 Resolution by chiral prep-HPLCRacemization - 6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di Hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (222 mg) resulting in a white solid (R ) -6-ethoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (20 mg) and white solid (S ) -6-ethoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (20 mg).step 2 (R ) -6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method F Synthesized in to deliver the desired product (5.0 mg, yield: 14%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.58 (d,J = 10.0 Hz, 1H), 4.36 (d,J = 11.2 Hz, 1H), 4.27-4.24 (m, 1H), 4.18-4.15 (m, 2H), 3.59 (q,J = 7.2 Hz, 2H), 2.79 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.99-1.91 (m, 4H), 1.09 (t,J = 6.8 Hz, 3H). MS: m / z 447.1 (M + H+ ). (S ) -6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7 -Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is prepared using the same procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.59 (d,J = 11.6 Hz, 1H), 4.37 (d,J = 11.6 Hz, 1H), 4.27-4.23 (m, 1H), 4.17-4.15 (m, 2H), 3.53 (q,J = 7.2 Hz, 2H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.98-1.91 (m, 4H), 1.08 (t,J = 7.2 Hz, 3H). MS: m / z 447.1 (M + H+ ).Examples 39 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-isopropoxy-6, Synthesis of 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 To a solution of dimethyl malonate (5.0 g, 38.0 mmol) and TEA (7.7 g, 76.0 mmol) in MeCN (80 mL) was added 4-acetamidobenzenesulfonyl azide (9.1 g, 38.0 mmol) and the reaction was stirred at room temperature for 16 hr. The reaction was filtered and the filtrate was partitioned between water (80 mL) and EA (80 mL). The organic layer was washed with brine (80 mL),2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 10/1) to give dimethyl 2-diazomalonate (3.9 g, yield: 53%) as a yellow oil.step 2 Dimethyl 2-diazomalonate (3.4 g, 21.5 mmol) and Rh2 (Ac)4 (36 mg, 0.2 mmol) in DCM (10 mL) was added i-PrOH (132.0 g, 0.2 mol) and the reaction was stirred at 70 ° C for 4 hr. The reaction was concentrated to dryness. The residue was purified by a silica gel column (PE / EA = 10/1), thereby producing dimethyl 2-isopropoxymalonate (3.7 g, yield: 90%) as a colorless oil.1 H NMR (300 MHz, CDCl3 ): δ = 4.60 (s, 1H), 3.81-3.74 (m, 7H), 1.26 (d,J = 6.0 Hz, 6H).step 3 To a solution of dimethyl 2-isopropoxymalonate (3.7 g, 19.4 mmol) in anhydrous THF (30 mL) at 0 ° C was added LiBH4 (2 M in THF, 19.4 mL, 38.7 mol) and the reaction was stirred at room temperature for 2 hr. Will be reacted by H2 O (20 mL) was quenched and the mixture was dried over MgSO4 dry. The reaction was filtered and the filtrate was concentrated to dryness to give 2-isopropoxypropane-1,3-diol (2.5 g, yield: 96%) as a colorless oil.1 H NMR (300 MHz, CDCl3 ): δ = 3.72-3.50 (m, 6H), 1.26 (t,J = 5.4 Hz, 2H), 1.22 (d,J = 6.0 Hz, 6H).step 4 To a solution of 2-isopropoxypropane-1,3-diol (2.5 g, 18.7 mmol) and TEA (5.7 g, 56.0 mmol) in anhydrous THF (30 mL) was added MsCl (4.7 g, 41.0 mmol). After stirring at room temperature for 2 hr, the reaction was filtered. The filtrate was concentrated to dryness to give crude 2-isopropoxypropane-1,3-diyl dimethanesulfonate as a white solid, which was used in the next step without any purification.step 5 Diisopropane-1,3-diyl dimethanesulfonate (crude, about 18.7 mmol), 1,2-dihydro-pyrazol-3-one (1.6 g, 18.7 mmol) and K2 CO3 A mixture of (7.7 g, 56.0 mmol) in DMF (40 mL) was heated to 100 ° C and held for 16 hr. The reaction was cooled and partitioned between EA (150 mL) and water (200 mL) and the layers were separated. The organic layer was washed with water (80 mL) and brine (50 mL).2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/2) to give 6-isopropoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] oxazine (2.1 g, yield: 88%).1 H NMR (300 MHz, CDCl3 ): δ = 7.33 (s, 1H), 5.49 (s, 1H), 4.31-3.84 (m, 5H), 3.84-3.80 (m, 1H), 1.22-118 (m, 6H). MS: m / z 183.3 (M + H+ ).step 6 N at 0 ° C2 Descend 6-isopropoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (1.0 g, 7.8 mmol) in a solution of MeCN. NBS (1.5 g, 8.6 mmol) was added in two portions. The reaction was then stirred at room temperature for 2 hr. The reaction was partitioned between EA (40 mL) and water (40 mL). The organic layer was washed with water (40 mL) and brine (40 mL).2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 2/1) to give 3-bromo-6-isopropoxy-6,7-dihydro-5H-pyrazolo [5,1 as a yellow solid -b] [1,3] oxazine (1.2 g, yield: 75%). MS: m / z 261.2 (M + H+ ).step 7 6-isopropoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl ester useManufacturing method B Synthesis, resulting in a yellow gel-like product, which was used in the next step without any purification. 6-isopropoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method C Medium synthesis, resulting in the desired product as a yellow solid (110 mg, yield: 22% over 2 steps). MS: m / z 262.3 (M + H+ ).step 8 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-isopropoxy-6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamideManufacturing method A Synthesized to deliver the desired product as a white solid (18 mg, yield: 10%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.47 (brs, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.49-4.46 (m, 1H), 4.37 (d,J = 12.0 Hz, 1H), 4.28-4.24 (m, 2H), 4.09-4.06 (m, 1H), 3.87-3.81 (m, 1H), 2.77 (t,J = 8.0 Hz, 4H), 2.61 (overlap, 4H), 1.97-1.91 (m, 4H), 1.09-1.05 (m, 6H). MS: m / z 461.1 (M + H+ ).Examples 40 Shown belowRacemization - ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamino) -6,7 -Synthesis of dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium. step 1 To a solution of 2-aminopropane-1,3-diol (10.0 g, 0.1 mol) in EtOH (100 mL) was added di-t-butyl dicarbonate (24.0 g, 0.1 mol). The reaction was stirred at room temperature for 16 hr. The reaction solution was concentrated to dryness in vacuo to give (1,3-dihydroxyprop-2-yl) aminocarboxylic acid third butyl ester (21.0 g, yield: 100%) as a white solid.step 2 To (1,3-dihydroxyprop-2-yl) aminocarboxylic acid tert-butyl ester (21.0 g, 0.1 mol) and TEA (23.0 g, 0.2 mol) in anhydrous CH at 0 ° C2 Cl2 (200 mL) was added MsCl (26.0 g, 0.2 mol). After stirring at room temperature for 2 hr, the reaction was filtered. The filtrate was concentrated to dryness to give crude 2-((third-butoxycarbonyl) amino) propane-1,3-diyl ester (37.0 g, yield: 97%) as a white solid, It was used in the next step without any purification.step 3 Dimethyl methanesulfonate 2-((third butoxycarbonyl) amino) propane-1,3-diyl ester (37.3 g, 0.11 mol), 1H-pyrazole-3 (300 mL) 2H) -one (9.0 g, 0.11 mol) and K2 CO3 (30.0 g, 0.22 mol) was heated at 120 ° C for 16 hr. After concentration, the residue was partitioned between EA (300 mL) and water (500 mL). The aqueous layer was extracted with EA (300 mL). The combined organic layers were washed with brine (100 mL),2 SO4 Dry, filter and concentrate to dryness in vacuo to give a yellow solidRacemization - (6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (8.8 g, yield: 34%) . MS: m / z 240.0 (M + H+ ).step 4 At 0 ℃Racemization - (6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (8.8 g, 37.0 mmol) in MeCN ( 100 mL) was added portionwise to NBS (6.5 g, 37.0 mmol) and the reaction was stirred at room temperature for 2 hr. The reaction mixture was concentrated. Purification of the residue by a silica gel column (PE / EA = 5/1) gave a yellow solidRacemization - (3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (2.5 g, yield :twenty one%). MS: m / z 319.9 (M + H+ ).step 5 toRacemization - (3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (900 mg, 2.8 mmol ) To a solution in DMF (10 mL) was added NaH (60% in mineral oil, 226 mg, 5.7 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. Then methyl iodide (2.0 g, 14.2 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (60 mL) and extracted with EA (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL).2 SO4 Dry and concentrate. By reversed-phase HPLC (MeCN / H2 O) Purification of the residue to give a yellow solidRacemization - (3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (methyl) aminocarboxylic acid third butyl ester (550 mg, yield: 59%).1 H NMR (300 MHz, CDCl3 ): δ = 7.36 (s, 1H), 4.6 (br, 1H), 4.38-4.29 (m, 4H), 2.82 (d,J = 3.6 Hz, 3H), 1.50 (s, 9H). MS: m / z 333.9 (M + H+ ).step 6 Racemization - 6-((third butoxycarbonyl) (methyl) amino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl esterManufacturing method B Synthesized to give a yellow oily product which was used in the next step without any purification.step 7 willRacemization - 6-((third butoxycarbonyl) (methyl) amino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4,6-trichlorophenyl ester (crude) and NH3 .H2 A solution of O (3.0 mL) in THF (5.0 mL) was stirred at 60 ° C for 16 hr. The mixture was concentrated in vacuo. Using a silica gel column (CH2 Cl2 / MeOH = 25/1) purifying the residue to give methyl (3-aminesulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] as a colorless oil Triazine-6-yl) aminocarbamate tert-butyl ester (26.0 mg, yield: 8%, 2 steps).1 H NMR (400 MHz, CDCl3 ): δ = 7.64 (s, 1H), 5.14 (br, 2H), 4.68 (br, 1H), 4.53-4.44 (m, 2H), 4.38-4.26 (m, 2H), 2.84 (s, 3H), 1.48 (s, 9H). MS: m / z 276.9 (M-56 + H+ ).step 8 (3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylfluorenyl) aminesulfonyl) -6, 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (meth) aminocarboxylic acid third butyl ester isManufacturing method D Medium synthesis, resulting in the desired product as a white solid (40 mg, yield: 95%). MS: m / z 476.0 (M-55- ).step 9 To (3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylsulfanyl) aminesulfonyl) -6 , 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (methyl) aminocarboxylic acid third butyl ester (40 mg, 0.08 mmol) in CH2 Cl2 (2 mL) was added to TFA (0.6 mL) and the mixture was stirred at room temperature for 30 min. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with a 2 M NaOH solution to a pH> 13. By reversed-phase HPLC (MeCN / H2 O) Purify the resulting solution to give a white solidRacemization - ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamino) -6,7 -Sodium dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfofluorenyl) phosphonium sodium (25.0 mg, 78%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.33 (s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.25-4.10 (m, 3H), 3.83-3.79 (m, 1H), 3.07 (m, 1H), 2.77-2.73 (m, 4H), 2.67-2.63 (m, 4H), 2.33 (s, 3H), 1.92-1.88 (m, 4H). MS: m / z 432.1 (M + H+ ).Examples 41 Shown below (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamino) -6 , 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium and (S )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamino) -6 Synthesis of 7,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium. step 1 Resolution by chiral prep-HPLCRacemization - N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6- (methylamino) -6, 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (400 mg, 1.2 mmol), resulting in a white solid (R ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6- (methylamino)- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (240 mg, yield: 60%) and white solid (S ) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6- (methylamino)- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (150 mg, yield: 37%).step 2 : (R )-(3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfamoyl)- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (meth) aminocarboxylic acid third butyl ester isManufacturing method D Medium synthesis, resulting in the desired product as a white solid (200 mg, yield: 52%). (S )-(3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfamoyl)- The 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (meth) carbamic acid third butyl ester was prepared using the same procedure.step 3 to(R )-(3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfamoyl)- 6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (methyl) aminocarboxylic acid third butyl ester (250 mg, 0.75 mmol) In CH2 Cl2 (5 mL) was added to TFA (2 mL) and the mixture was stirred at room temperature for 30 min. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with a 2 M NaOH solution to a pH> 13. By reversed-phase HPLC (MeCN / H2 O) Purify the resulting solution to give a white solid (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamino) -6 , 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium (130 mg, 30%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.50 (s, 1H), 7.38 (s, 1H), 6.8 (s, 1H), 4.28 (dd,J = 10.8 Hz, 2.4Hz, 1H), 4.20-4.10 (m, 2H), 3.85 (dd,J = 11.6 Hz, 4.8Hz, 1H), 3.14-3.06 (m, 1H), 2.76 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.33 (s, 3H), 1.97-1.86 (m, 4H). MS: m / z 432.1 (M + H+ ). (S )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamino) -6 Sodium, 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) fluorenamide sodium was prepared using the same procedure.1 H NMR (400 MHz, DMSO-d6 ): δ = 7.35 (s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.27-4.21 (m, 1H), 4.17-4.12 (m, 1H), 4.08-4.05 (m, 1H ), 3.84-3.77 (m, 1H), 3.11-3.03 (m, 1H), 2.76 (t,J = 8.0 Hz, 4H), 2.65 (t,J = 7.6 Hz, 4H), 2.33-2.27 (m, 3H), 1.97-1.83 (m, 4H). MS: m / z 432.1 (M + H+ ).Examples 42 Shown below (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamino) -6 Synthesis of 7,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) fluorenamine. step 1 In N2 1-Ethyl-1,2-dihydro-pyrazol-3-one (10.0 g, 0.79 mmol), (S ) -Ethylene-2-ylmethanol (7.0 g, 95 mmol) and PPh3 A mixture of (31.0 g, 118.5 mmol) in THF (100 mL) was cooled to 0 ° C. To the mixture was slowly added DIAD (23.3 mL, 118.5 mmol) in THF (25 mL). The reaction was stirred for an additional hour at 0 ° C. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by a silica gel column (PE / EA = 10/1) to give a white solid (S ) -1-Ethyl-2- (epoxyethyl-2-ylmethyl) -1H -Pyrazole-3 (2H ) -Ketone (10.1 g, yield: 70%).1 H NMR (400 MHz, CDCl3 ): δ = 8.07 (d,J = 2.8 Hz, 1H), 6.00 (d,J = 2.8 Hz, 1H), 4.56-4.51 (m, 1H), 4.21-4.15 (m, 1H), 3.41-3.34 (m, 1H), 2.93-2.89 (m, 1H), 2.77-2.74 (m, 1H ), 2.58 (s, 3H).step 2 At 0 ° CS ) -1-Ethyl-2- (epoxyethyl-2-ylmethyl) -1H -Pyrazole-3 (2H ) -Ketone (55.0 g, 300 mmol) in a solution of AcOH (52 mL, 900 mmol) and THF (250 mL) was added in portions of LiCl.H2 O (29.0 g, 480 mmol). The reaction was then stirred at room temperature overnight. After removing AcOH and THF in vacuo, the residue was partitioned between EA (200 mL) and water (200 mL). The aqueous layer was extracted with EA (50 mL × 4). Combine the combined organic layers with saturated NaHCO3 The solution was washed with brine (100 mL) and washed with Na2 SO4 Dry and concentrate in vacuo to give a colorless oily crude (S ) -1-Ethyl-2- (3-chloro-2-hydroxypropyl) -1H -Pyrazole-3 (2H ) -One (59.0 g, 90%), which was used in the next step without any purification.1 H NMR (400 MHz, CDCl3 ): δ = 8.07 (d,J = 3.2 Hz, 1H), 6.00 (d,J = 3.2 Hz, 1H), 4.41 (d,J = 4.8 Hz, 2H), 4.28-4.20 (m, 1H), 3.78-3.64 (m, 2H), 2.58 (s, 3H).step 3 will(S ) -1-Ethyl-2- (3-chloro-2-hydroxypropyl) -1H -Pyrazole-3 (2H ) -Ketone (65.4 g, 0.3 mol), K2 CO3 A mixture of (82.8 g, 0.6 mol) and KI (9.96 g, 60 mmol) in DMF (500 mL) was stirred at 130 ° C overnight. The solvent was removed under reduced pressure. The residue was purified by a silica gel column (EA) to give a white solid (S ) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-ol (27.6 g, yield: 66%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.22 (d,J = 2.0 Hz, 1H), 5.44 (d,J = 2.0 Hz, 1H), 4.28-4.09 (m, 4H), 3.94-3.87 (m, 1H).step 4 to(S ) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-ol (28.0 g, 0.2 mol) in a solution of pyridine (200 mL) Methanesulfonyl chloride (23.0 g, 0.2 mol). The reaction was stirred at room temperature for 30 min. The reaction solution was concentrated to dryness in vacuo and the residue was partitioned between EA (300 mL) and water (500 mL). The aqueous layer was extracted with EA (300 mL). The combined organic layers were washed with brine (100 mL),2 SO4 Dried, filtered and concentrated to dryness in vacuo to give a white solid (S ) -Methanesulfonic acid 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl ester (44.0 g, yield: 99%) Any purification was used in the next step.step 5 will(S ) -Methanesulfonic acid 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl ester (44.0 g, 0.2 mol) and NaN3 A mixture of (26.0 g, 0.4 mol) in anhydrous DMF (300 mL) was stirred at 120 ° C for 2 hr. The mixture was then used directly in the next step without any purification.step 6 will(R ) -6-azido-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (crude solution in DMF), Boc2 A solution of O (44 g, 0.2 moL) and Pd / C (3.0 g) in MeOH (300 mL) was stirred at room temperature under a hydrogen atmosphere (50 Psi) for 16 hr. The reaction mixture was filtered and concentrated to dryness in vacuo. The residue was purified by a silica gel column (PE / EA = 1/1) to give a white solid (R )-(6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (30 g, 63%).step 7 At 0 ° CR )-(6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (14.0 g, 60.0 mmol) To a solution in MeCN (200 mL) was added NBS (10.7 g, 60.0 mmol) in portions and the reaction was stirred at room temperature for 2 hr. After filtration, the filtrate was concentrated. The residue was purified by a silica gel column (PE / EA = 1/2) to give a yellow solid (R )-(3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (20.5 g, Crude). MS: m / z 320.0 (M + H+ ).step 8 to(R )-(3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (20.5 g, 64.4 mmol) To a solution in DMF (150 mL) was added NaH (60% in mineral oil, 5.2 g, 130.0 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. Then methyl iodide (46.0 g, 320.0 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (300 mL) and extracted with EA (300 mL). The organic layer was washed with water (150 mL), brine (50 mL), and dried over Na2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 3/1) to give a white solid (R )-(3-bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (methyl) aminocarboxylic acid third butyl ester (18 g, yield: 90%). MS: m / z 334.0 (M + H+ ).step 9 (R ) -6-((third butoxycarbonyl) (methyl) amino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3- 2,4,6-trichlorophenyl sulfonateManufacturing method B Synthesized to give a yellow oily product which was used in the next step without purification.step 10 will(R ) -6-((third butoxycarbonyl) (methyl) amino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3- 2,4,6-trichlorophenyl sulfonate (crude) and NH3 .H2 A solution of O (12.0 mL) in THF (50.0 mL) was stirred at 60 ° C for 16 hr. The mixture was concentrated in vacuo. The residue was purified by a silica gel column (DCM / MeOH = 25/1) to give a yellow solid (R ) -Methyl (3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid tert-butyl Ester (1.8 g, yield: 25%, 2 steps). MS: m / z 333.1 (M + H+ ).step 11 (R )-(3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfamoyl)- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (meth) aminocarboxylic acid third butyl ester isManufacturing method D Medium synthesis, resulting in the desired product as a yellow solid (230 mg, yield: 96%).step 12 to(R )-(3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfamoyl)- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (meth) aminocarboxylic acid third butyl ester (230 mg, 0.43 mmol) In CH2 Cl2 (2 mL) was added to TFA (0.6 mL) and the mixture was stirred at room temperature for 30 min. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with a 2 M NaOH solution to a pH> 13. By reversed-phase HPLC (0% -50% H2 MeCN in O) purified the resulting solution to give (s)-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amine as a white solid (Methylamino) ((6- (methylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) Ammonium sodium (150.0 mg, 80%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.41 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 4.26 (d,J = 9.2 Hz, 1H), 4.19-4.07 (m, 2H), 3.84-3.80 (m, 1H), 3.09 (br, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 2.34 (s, 3H), 1.94-1.87 (m, 4H). MS: m / z 432.1 (M + H+ ).Examples 43 Shown belowRacemization - 6- (ethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6, Synthesis of 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 ~ 3 The three steps are similar to ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl), ((6- (methylamine General procedure for -6-, 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide.step 4 Racemization - Ethyl (3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfonyl)- 6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester isManufacturing method F Synthesized in to deliver the desired product (100 mg, yield: 64%) as a white solid. MS: m / z 546.3 (M + H+ )step 5 toRacemization - Ethyl (3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfonyl)- 6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (100 mg, 0.2 mmol) in CH2 Cl2 (2 mL) was added to TFA (1 mL) and the mixture was stirred at room temperature for 30 min. The mixture was then concentrated to remove the solvent. Combine the residue with CH2 Cl2 (5 mL x 3) co-evaporated and subsequently by reverse phase HPLC [0% -95% H2 MeCN in O (0.1% NH3 .H2 O)] purified to give a white solidRacemization - 6- (ethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6, 7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (60 mg, 73%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.91 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.41 (dd,J = 11.2, 2.4 Hz, 1H), 4.31 (dd,J = 10.8, 4.8 Hz, 1H), 4.24 (dd,J = 12.8, 4.4 Hz, 1H), 3.95 (dd,J = 12.8, 4.4 Hz, 1H), 3.33 (overlapping, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.68-2.58 (m, 6H), 2.00-1.91 (m, 4H), 1.01 (t,J = 7.2 Hz, 3H). MS: m / z 446.1 (M + H+ ).Examples 44 Shown below (R ) -6- (ethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide hydrochloride and (S ) -6- (ethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)- Synthesis of 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfamethoxamine hydrochloride. step 1 Resolution by chiral prep-HPLCRacemization - Ethyl (3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester ( 120 mg), resulting in (R ) -Ethyl (3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid tert-butyl Esters (peak 1, 52 mg) and (S ) -Ethyl (3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid tert-butyl Ester (peak 2, 48 mg).step 2 This step is similar toRacemization - 6- (ethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6, General procedure for 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide.step 3 to(R ) -Ethyl (3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) sulfamoyl ) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (40 mg, 0.1 mmol) in CH2 Cl2 (2 mL) was added to TFA (1 mL) and the mixture was stirred at room temperature for 30 min. The mixture was then concentrated to remove the solvent. Combine the residue with CH2 Cl2 (5 mL x 3) co-evaporated and subsequently with saturated NaHCO3 Neutralize to pH = 8. The resulting solution was acidified with aq. HCl (2 N) to pH = 5 and then by reverse phase HPLC [0% -95% H2 MeCN in O] was purified to give a white solid (R ) -6- (ethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfamethoxamine hydrochloride (15 mg, 22%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.74 (s, 1H), 7.52 (s, 1H), 6.88 (s, 1H), 4.38-4.33 (m, 1H), 4.24-4.17 (m, 2H), 3.92-3.85 (m, 1H ), 3.32 (overlapping, 1H), 2.77 (t,J = 7.2 Hz, 4H), 2.64-2.59 (m, 6H), 2.00-1.89 (m, 4H), 1.00 (t,J = 7.2 Hz, 3H). MS: m / z 446.1 (M + H+ ). (S ) -6- (ethylamino) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)- 6,7-Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide was prepared using the same procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.89 (s, 1H), 7.60 (s, 1H), 6.93 (s, 1H), 4.41 (dd,J = 10.8, 2.4 Hz, 1H), 4.31 (dd,J = 10.8, 5.2 Hz, 1H), 4.24 (dd,J = 12.4, 4.4 Hz, 1H), 3.95 (dd,J = 12.4, 4.4 Hz, 1H), 3.00 (overlap, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.63-2.58 (m, 6H), 1.97-1.93 (m, 4H), 1.01 (t,J = 7.2 Hz, 3H). MS: m / z 446.1 (M + H+ ).Examples 45 Shown below (R )-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamine Synthesis of 6), 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide. step 1 N at -10 ℃2 Downward 1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-amine (3.0 g, 17.3 mmol) in THF / H2 O / HBF4 (45 mL / 7mL / 22mL), add NaNO dropwise to the solution2 (1.3 g, 18.2 mmol) in H2 O (3 mL). After stirring for 2 hr under cooling, the cold bath was removed and the reaction was partitioned between water (100 mL) and EA (100 mL). Use organic layer with NaHCO3 (50 mL), brine (50 mL), and Na2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE) to produce 4-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadiene benzene (1.4 g, product Rate: 46%).1 H NMR (300 MHz, CDCl3 ): δ = 6.88 (s, 1H), 2.92-2.87 (m, 8H), 2.17-2.07 (m, 4H).step 2 N at 0 ° C2 Downward solution of 4-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadiene benzene (1.4 g, 8.0 mmol) in MeCN (20 mL), take NO2 BF4 (1.3 g, 9.8 mmol) was added in two portions. The reaction was then stirred at 0 ° C for 1 hr. The reaction was partitioned between EA (100 mL) and water (100 mL). The organic layer was washed with water (20 mL) and brine (20 mL).2 SO4 Dry and concentrate. Purification of the residue by a silica dioxide flash boiling tower (0% ~ 45% EA in PE) gave 4-fluoro-8-nitro-1,2,3,5,6,7-hexa as a white solid Hydrogen-s-dicyclopentadiene benzene (1.4 g, yield: 80%).1 H NMR (400 MHz, CDCl3 ): δ = 3.30 (t,J = 6.8 Hz, 4H), 2.95 (t,J = 7.6 Hz, 4H), 2.22-2.13 (m, 4H).step 3 4-Fluoro-8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadiene benzene (1.4 g, 6.3 mmol) in MeOH (20 mL) Add 10% Pd / C (200 mg). After stirring at room temperature under a balloon hydrogen atmosphere overnight, the reaction mixture was filtered. The filtrate was evaporated to dryness in vacuo and the residue was purified by a silica dioxide boiling tower (EA in 0% to 45% PE) to give 8-fluoro-1,2,3,5,6 as a white solid , 7-hexahydro-s-dicyclopentadienebenzo-4-amine (1.1 g, yield: 91%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 4.42 (s, 2H), 2.75 (t,J = 7.6 Hz, 4H), 2.62 (t,J = 7.6 Hz, 4H), 2.05-1.97 (m, 4H). MS: m / z 192.4 (M + H+ ).step 4 (R )-(3- (N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamidino) amine (Fluorenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (meth) aminocarboxylic acid third butyl ester isManufacturing method D Medium synthesis, resulting in the desired product as a yellow solid (1.8 g, yield: 72%). MS: m / z 550.2 (M + H+ ).step 5 to(R )-(3- (N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamidino) amine Fluorenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) (methyl) aminocarboxylic acid third butyl ester (1.8 g , 3.3 mmol) in CH2 Cl2 (8 mL) was added to the solution in TFA (8 mL) and the mixture was stirred at room temperature for 30 min. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with 2 N aq. NaOH to a pH> 13. By reversed-phase HPLC (MeCN / H2 O) Purify the resulting solution to give a yellow solid (R )-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (methylamine ) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide (1.2 g, 80%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.32 (s, 1H), 4.28-4.24 (m, 1H), 4.16 (q,J = 4.8 Hz, 1H), 4.09 (q,J = 6.0 Hz, 1H), 3.82 (q,J = 5.2 Hz, 1H), 3.08 (br, 1H), 2.78 (t,J = 7.6 Hz, 4H), 2.71 (t,J = 7.6 Hz, 4H), 2.33 (s, 3H), 1.99-1.93 (m, 4H). MS: m / z 450.1 (M + H+ ).Examples 46 Shown below (R ) -N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy Synthesis of -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide.to(R ) -6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (80 mg, 0.34 mmol) in THF MeONa (54 mg, 1.0 mmol) was added to the solution in (10 mL) and the mixture was stirred at room temperature for 30 min, resulting in a sodium salt suspension. In another flask, add 8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-amine (66 mg, 0.34 mmol) and TEA (102 mg, 1 mmol) in THF (10 mL) was added triphosgene (40 mg, 0.14 mmol) in one portion and the mixture was stirred at room temperature under N2 Stir for 30 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature overnight. Thereafter, the reaction solution was partitioned between EA (10 mL) and water (5 mL). The aqueous phase was acidified to pH = 5 with 1 N HCl. The formed solid was collected by filtration and dried to give a white solid (R ) -N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (27 mg, yield: 17.6%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.55 (brs, 1H), 7.91 (brs, 1H), 7.61 (s, 1H), 4.62 (d,J = 11.6 Hz, 1H), 4.35 (d,J = 11.6 Hz, 1H), 4.18-4.27 (m, 2H), 4.06 (s, 1H), 3.35 (s, 3H), 2.82 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.6 Hz, 4H), 1.98-2.05 (m, 4H) MS: m / z 450.8 (M + H+ ).Examples 47 Shown below (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (prop-2-yne-1 -Methoxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide sodium. step 1 toRacemization - N, N-dibenzyl-6- (3-hydroxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine To a solution of -3-sulfamethoxamine (840 mg, 2.1 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 126.0 mg, 3.2 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. 3-Bromoprop-1-yne (273.0 mg, 2.3 mmol) was then added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL).2 SO4 Dry and concentrate to dryness to give a yellow solidRacemization - N, N-dibenzyl-6- (prop-2-yn-1-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine -3-sulfamethoxamine (580 mg, yield: 63%).1 H NMR (300 MHz, CDCl3 ): δ = 7.63 (s, 1H), 7.25-7.16 (m, 10H), 4.52-4.17 (m, 11H), 2.55 (s, 1H). MS: m / z 438.1 (M + H+ ).step 2 toRacemization - N, N-dibenzyl-6- (prop-2-yn-1-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine -3-sulfamethoxamine (115 mg, 0.3 mmol) in CH2 Cl2 (3.0 mL) add concentrated H to the stirred solution2 SO4 (16 drops, 0.32 mL) and stirred at 0 ° C for 10 min. The reaction solution was concentrated. The residue was saturated with NaHCO3 Neutralize the solution. The solid was then filtered from the mixture and reversed-phase HPLC (MeCN / H2 O) Purify the filtrate to give a yellow solidRacemization - 6- (prop-2-yn-1-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (23.0 mg, yield: 34%). MS: m / z 258.0 (M + H+ ).step 3 Racemization - ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (prop-2-yn-1-yl (Oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfofluorenyl) fluorenamines such asManufacturing method D Medium synthesis, resulting in the desired product as a white solid (20.0 mg, yield: 49%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (brs, 1H), 7.85 (s, 1H), 6.92 (s, 1H), 4.63-4.59 (m, 1H), 4.40-4.25 (m, 6H), 3.52 (t,J = 2.4 Hz, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.62 (t,J = 7.2 Hz, 4H), 1.99-1.92 (m, 4H). MS: m / z 457.1 (M + H+ ).Examples 48 Shown belowRacemization - ((6-(((Third butoxycarbonyl) (methyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Azin-3-yl) sulfofluorenyl) (Sodium ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) synthesis. step 1 At 0 ℃Racemization - ((3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) aminocarboxylic acid third butyl ester (0.3 g, 0.9 mmol) in THF (3 mL) was added NaH (60%, 108 mg, 2.7 mmol), followed by MeI (639 mg, 4.5 mmol). After stirring for 16 hr at room temperature, the suspension was quenched with the addition of EA (20 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with EA (10 mL). The organic layers were combined, washed with brine (10 mL),2 SO4 Dry and concentrate in vacuo. Purification of the residue by a silica gel column (PE / EA = 2/1) gave a yellow oilRacemization - (((3-Bromo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) (methyl) aminocarbamic acid Ester (290 mg, yield: 93%).step 2 Racemization - 6-(((third-butoxycarbonyl) (methyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- 3-sulfonic acid 2,4,6-trichlorophenyl esterManufacturing method B Synthesized to give a yellow oily product which was used in the next step without purification.step 3 Racemization - Methyl ((3-Aminosulfonyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-6-yl) methyl) carbamic acid Butyl esters such asManufacturing method C Medium synthesis, resulting in the desired product as a pale yellow solid (60 mg, yield: 16% over 2 steps). MS: m / z 369.4 (M + Na+ ).step 4 ((6-(((Third butoxycarbonyl) (methyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Azine-3-yl) sulfofluorenyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamido) sulfonamide sodium Such asManufacturing method D Medium synthesis, resulting in the desired product as a white solid (28 mg, yield: 31%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.33 (s, 1H), 7.31 (s, 1H), 6.75 (s, 1H), 4.28 (d,J = 10.4 Hz, 1H), 4.10-4.0 (m, 2H), 3.80-3.73 (m, 1H), 3.25-3.15 (m, 2H), 2.80 (s, 3H), 2.74 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 2.50 (overlapping, 1H), 1.95-1.85 (m, 4H), 1.41-1.31 (m, 9H). MS: m / z 546.2 (M + H+ ).Examples 49 The following shows ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-((methylamino) methyl Synthesis of 6), 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide.toRacemization - ((6-(((Third butoxycarbonyl) (methyl) amino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Azine-3-yl) sulfofluorenyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamido) sulfonium sodium ( 15 mg, 0.03 mmol) in CH2 Cl2 (2 mL) was added to TFA (0.6 mL) and the mixture was stirred at room temperature for 30 min. The mixture was then concentrated in vacuo to remove the solvent. The residue was added to a 2 N NaOH solution to a pH> 13. By reversed-phase HPLC (MeCN / H2 O) Purify the resulting solution to give a white solidRacemization - ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-((methylamino) methyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium (10 mg, 80%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.36 (s, 1H), 6.77 (s, 1H), 4.39 (dd,J = 11.2 Hz, 2.8 Hz, 1H), 4.20-4.1 (m, 2H), 3.83 (dd,J = 12.4 Hz, 7.6 Hz, 1H), 3.42 (m, 5H), 3.16-3.11 (m, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 1.96-1.86 (m, 4H). MS: m / z 446.1 (M + H+ ).Examples 50 Shown below (R ) -6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide and (S ) -6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7- Synthesis of Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 N at 0 ° C2 LiBH was added dropwise to a solution of dimethyl 2-ethylmalonate (1.8 g, 9.6 mmol) in THF (10 mL) under an atmosphere.4 (2 M in THF, 9.6 mL, 19.2 mmol). The reaction mixture was stirred at room temperature for 16 hr and then poured into water (40 mL). The resulting solution was concentrated to approximately 5 mL and mixed with EA (50 mL). The mixture was stirred vigorously for 5 min with MgSO4 Dry and concentrate to give 2-ethylpropane-1,3-diol (970 mg, yield: 97%) as a colorless oil.step 2 To 2-ethylpropane-1,3-diol (970 mg, 9.3 mol) and Et at 0 ° C3 To a solution of N (2.4 g, 23.8 mmol) in anhydrous THF (20 mL) was added MsCl (2.2 g, 19.3 mmol). After stirring at room temperature for 30 min, the reaction mixture was filtered. The filtrate was concentrated to dryness to give crude 2-ethylpropane-1,3-diyl dimethanesulfonate as a yellow oil.step 3 Diethyl methanesulfonate 2-ethylpropane-1,3-diyl ester (crude), 1H-pyrazole-3 (2H) -one (750 mg, 8.9 mmol) and K2 CO3 A mixture of (4.3 g, 31.2 mmol) in DMF (40 mL) was heated at 100 ° C for 16 hr. Partition the reaction mixture in EA / H2 O (80 mL / 200 mL) and separate the layers. The aqueous layer was extracted with EA (80 mL x 3) and the combined organic layers were washed with brine (50 mL),2 SO4 Dry and concentrate. Purification of the residue by a silica gel column (PE / EA = 3/1) gave a colorless oilRacemization - 6-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (650 mg, yield: 48%).1 H NMR (300 MHz, CDCl3 ): δ = 7.32 (d,J = 1.5 Hz, 1H), 5.48 (d,J = 1.5 Hz, 1H), 4.34-4.26 (m, 2H), 3.95-3.87 (m, 1H), 3.81-3.73 (m, 1H), 2.30-2.19 (m, 1H), 1.60-1.40 (m, 2H ), 1.05 (t,J = 7.5 Hz, 3H).step 4 At 0 ° CRacemization - 6-Ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine (650 mg, 4.3 mmol) was added dropwise to ClSO3 H (4 mL). After stirring at 80 ° C for 2 hr, the reaction mixture was added dropwise to a mixture of ice water / EA (30 mL / 20 mL). The layers were separated and the aqueous layer was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (20 mL),2 SO4 Dried and concentrated to give a crude yellow solidRacemization - 6-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride.step 5 CrudeRacemization - NH was added to a solution of 6-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonyl chloride in THF (3 mL)3 .H2 O (1 mL). After stirring at 60 ° C for 1 h, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH (3 mL) and acidified to pH = 3 with aq. HCl (1 N). By reversed-phase HPLC (0%-95% H2 MeCN in O) purified residue to give a yellow solidRacemization - 6-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (200 mg, yield: 20%, two steps ).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.48 (s, 1H), 7.08 (s, 2H), 4.48-4.44 (m, 1H), 4.21 (dd,J = 12.4, 5.6 Hz, 1H), 4.12-4.07 (m, 1H), 3.81-3.75 (m, 1H), 2.24-2.17 (m, 1H), 1.47-1.32 (m, 2H), 0.96 (t,J = 7.2 Hz, 3H).step 6 Separation by chiral HPLCRacemization - 6-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (200 mg), resulting in two isomers: (R ) -6-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (peak 1, 80 mg) and (S ) -6-ethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (peak 2, 83 mg).step 7 (S ) -6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamideManufacturing method A Synthesized to deliver the desired product as a white solid (53 mg, yield: 34%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (brs, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.51 (d,J = 2.8 Hz, 1H), 4.48-4.15 (m, 2H), 3.82-3.77 (m, 1H), 2.78 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.20-1.98 (m, 1H), 1.97-1.91 (m, 4H), 1.45-1.11 (m, 2H), 0.96 (t,J = 7.6 Hz, 3H). MS: m / z 431.1 (M + H+ ). (R ) -6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7- Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide was prepared using the same procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.46 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.50 (dd,J = 10.8, 3.2 Hz, 1H), 4.24-4.13 (m, 2H), 3.83-3.78 (m, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.59 (t,J = 7.2 Hz, 4H), 2.21-2.19 (m, 1H), 1.99-1.92 (m, 4H), 1.42-1.35 (m, 2H), 0.95 (t,J = 7.2 Hz, 3H). MS: m / z 431.1 (M + H+ ).Examples 51 The following shows 6- (3-fluoroazetidin-1-yl) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl ) Synthesis of carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2,4 1,6-trichloro-phenyl ester systemManufacturing method B Synthesized to give a yellow gel-like product which was used in the next step without purification.step 2 6- (tetrahydro-pyran-2-yloxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid 2, A mixture of 4,6-trichloro-phenyl ester (crude, about 6.6 mmol), dibenzylamine (2.5 g, 12.0 mmol) and THF (20 mL) was stirred at 60 ° C overnight. The reaction was concentrated under reduced pressure until 10 mL of liquid remained. The remaining solution was acidified with aq. HCl (1 N) to pH = 5 and extracted with EA (100 mL x 5). Combine the organic layers over Na2 SO4 Dry and concentrate to give N, N-dibenzyl-6-((tetrahydro-2H-pyran-2-yl) oxy) -6,7-dihydro-5H-pyrazolo [ 5,1-b] [1,3] oxazine-3-sulfonamide (1.5 g, yield: 51%). MS: m / z 484.2 (M + H+ ).step 3 N, N-dibenzyl-6-((tetrahydro-2H-pyran-2-yl) oxy) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] oxazine-3-sulfonamide (6.1 g, 12.6 mmol) in THF / H2 To a solution in O / EtOH (50 mL / 10 mL / 50 mL) was added concentrated HCl (10 mL) and the mixture was stirred at room temperature overnight. The reaction was concentrated under reduced pressure. By reversed-phase HPLC (MeCN / H2 O) Purification of the residue to give N, N-dibenzyl-6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- as a white solid 3-Sulfonamide (4.0 g, yield: 80%). MS: m / z 400.1 (M + H+ ).step 4 Add N, N-dibenzyl-6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (3.4 g, 8.5 mmol) and Dess-Martin periodiane (7.2 g, 17.0 mmol) in CH2 Cl2 (50.0 mL) was stirred at room temperature for 16 hr. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA = 1: 2) to give N, N-dibenzyl-6-sideoxy-6,7-dihydro-5H-pyrazole as a yellow solid. And [5,1-b] [1,3] oxazine-3-sulfonamide (3.0 g, yield: 91%).step 5 N, N-dibenzyl-6- pendantoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonium at room temperature To a stirred solution of amine (397.0 mg, 1.0 mmol) and 3-fluoroazetidine hydrochloride (224.0 mg, 2.0 mmol) in MeOH (10.0 mL) was added sodium triacetoxyborohydride (424.0 mg , 2.0 mmol). After stirring at room temperature for 30 min, sodium cyanotrihydroborate (126 mg, 2.0 mmol) was added to the mixture. The reaction was stirred at room temperature for 16 hr and concentrated in vacuo. By silica gel column chromatography (CH2 Cl2 / MeOH = 5/1) The residue was purified to give N, N-dibenzyl-6- (3-fluoroazetidin-1-yl) -6,7-dihydro-5H-pyridine as a yellow solid. Zolo [5,1-b] [1,3] oxazine-3-sulfonamide (160 mg, yield: 35%).step 6 N, N-dibenzyl-6- (3-fluoroazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Triazine-3-sulfamethoxamine (140 mg, 0.3 mmol) in CH2 Cl2 (3.0 mL) add concentrated H to the solution2 SO4 (16 drops, 0.32 mL) and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated. The residue was saturated with NaHCO3 The solution was neutralized and filtered. By reversed-phase HPLC (0% -95% H2 MeCN in O) purified the filtrate to give 6- (3-fluoroazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 as a yellow solid , 3] oxazine-3-sulfonamide (60.0 mg, yield: 71%).step 7 6- (3-fluoroazetidin-1-yl) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amine (Methylamino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamideManufacturing method F The synthesis was described as a white solid in the delivery phase (11.0 mg, yield: 11%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.48 (brs, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 6.93 (s, 1H), 5.20-5.17 (m, 0.5H), 5.06-5.03 (m, 0.5H ), 4.32 (q, J = 6.0 Hz, 2H), 4.17 (dd, J = 12.8, 4.0 Hz, 1H), 3.89 (d,J = 13.2 Hz, 1H), 3.65-3.60 (m, 2H), 3.28 (overlap, 2H), 3.09 (d,J = 4.0 Hz, 1H), 2.79 (t,J = 7.6 Hz, 4H), 2.61 (t,J = 7.6 Hz, 4H), 1.99-1.94 (m, 4H). MS: m / z 476.1 (M + H+ ).Examples 52 Shown below is ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (pyrrolidin-1-yl) Synthesis of -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium. step 1 To the 6-oxo-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonic acid dibenzylamidamine (750 mg, 1.9 mmol) And pyrrolidine (270 mg, 3.8 mmol) in MeOH (18 mL) was added with AcOH until pH = 6. NaBH (OAc) was subsequently added3 (810 mg, 3.8 mmol) and the reaction mixture was stirred at room temperature for 3 hr. Add NaBH3 CN (240 mg, 3.8 mmol) and the reaction mixture was stirred at room temperature for another 16 hr. The reaction solution was concentrated to about 6 mL and then by reversed-phase HPLC (0% -95% H2 MeCN in O) was purified to yield a 6-pyrrolidin-1-yl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- Dibenzylphosphonium 3-sulfonate (290 mg, yield: 34%). MS: m / z 453.1 (M + H+ )step 2 This step is similar to 6- (3-fluoroazetidin-1-yl) -N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-4 -Yl) Aminomethylamidino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. General procedure.step 3 6-pyrrolidin-1-yl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (50 mg, 0.2 mmol) To the suspension in THF (2 mL) was added MeONa (35 mg, 0.6 mmol) and the mixture was stirred at room temperature for 20 min, resulting in a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (30 mg, 0.2 mmol) and TEA (50 mg, 0.5 To a solution of THF (3 mL) in THF (3 mL) was added phosgene (20 mg, 0.1 mmol) in one portion and the mixture at room temperature under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above-mentioned sodium salt suspension. After stirring at room temperature for 16 hr, the reaction solution was partitioned between EA (10 mL) and water (30 mL). Pass the water phase through N2 Bubbling for 5 min and then by reverse phase HPLC (0% -95% H2 MeCN in O) was purified to give ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amine formamidine) as a white solid (( 6- (Pyrrolidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) phosphonium sodium ( 10 mg, yield: 12%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (s, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 4.50-4.40 (m, 2H), 4.27 (dd,J = 12.8, 4.0 Hz, 1H), 4.13 (dd,J = 12.8, 4.0 Hz, 1H), 2.94-2.91 (m, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.68-2.58 (m, 8H), 2.00-1.91 (m, 4H), 1.70-1.60 (m, 4H). MS: m / z 472.1 (M + H+ ).Examples 53 ((6- (azetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamidino) sulfonamideThe title compound uses ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (pyrrolidine-1- Group) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium. General procedure.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.33 (s, 1H), 6.77 (s, 1H), 4.15-4.02 (m, 3H), 3.75 (dd,J = 12.8, 1.6 Hz, 1H), 3.20 (t,J = 6.8 Hz, 4H), 2.84-2.80 (m, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 1.97-1.87 (m, 6H). MS: m / z 458.1 (M + H+ ).Examples 54 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6-methyl Synthesis of phenyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 N at -78 ° C2 TiCl downward4 (0.5 mL, excess) and a stirred solution of methyl magnesium bromide (1.0 mL, excess) in THF (5.0 mL) were added N, N-dibenzyl-6-oxo-6,7-dihydro -5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (140.0 mg, 0.4 mmol). The mixture was then filtered and passed through a silica gel column chromatography (CH2 Cl2 / MeOH = 25/1) The filtrate was purified to give N, N-dibenzyl-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b as a white solid ] [1,3] oxazine-3-sulfonamide (55 mg, yield: 38%).step 2 N, N-dibenzyl-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (55 mg, 0.1 mmol) in CH2 Cl2 (3.0 mL) add concentrated H to the stirred solution2 SO4 (8 drops, 0.16 mL) and stirred at room temperature for 30 min. The reaction solution was concentrated. The residue was saturated with NaHCO3 Neutralize the solution. The mixture was then filtered and reversed-phase HPLC (MeCN / H2 O) The filtrate was purified to give 6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonium as a white solid. Amine (26.0 mg, yield: 87%).step 3 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-hydroxy-6-methyl-6, 7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method F Synthesized in to deliver the desired product (7.0 mg, yield: 15%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.4 (s, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.45 (s, 1H), 4.18 (s, 2H), 4.04 (d,J = 12.4 Hz, 1H), 3.91 (d,J = 12.0 Hz, 1H), 2.79 (t,J = 7.2 Hz, 4H), 2.61 (t,J = 7.2 Hz, 4H), 1.99-1.92 (m, 4H), 1.25 (s, 3H). MS: m / z 433.1 (M + H+ ).Examples 55 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6-methyl Synthesis of phenyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 N, N-dibenzyl-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (35 mg, 0.08 mmol) in DMF (3 mL) was added with NaH (60% in mineral oil, 6.4 mg, 0.16 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. Then methyl iodide (60 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL).2 SO4 Dry and concentrate. By reversed-phase HPLC (MeCN / H2 O) Purification of the residue to give N, N-dibenzyl-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [ 1,3] oxazine-3-sulfonamide (30 mg, yield: 83%).1 H NMR (300 MHz, CDCl3 ): δ = 7.58 (s, 1H), 7.29-7.26 (m, 5H), 7.18-7.15 (m, 5H), 4.34 (s, 4H), 4.21 (s, 3H), 4.16 (s, 2H), 2.67 (s, 2H), 1.38 (s, 3H). MS: m / z 428.0 (M + H+ ).step 2 N, N-dibenzyl-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonate Amidine (25 mg, 0.06 mmol) in CH2 Cl2 (3.0 mL) add concentrated H to the stirred solution2 SO4 (8 drops, 0.16 mL) and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated. The residue was saturated with NaHCO3 Neutralize the solution. The mixture was then filtered and reversed-phase HPLC (MeCN / H2 O) Purify the filtrate to give 6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3- as a yellow solid Sulfonamide (6.0 mg, yield: 35%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.57 (s, 1H), 4.09 (s, 3H), 3.89 (q,J = 10.4 Hz, 2H), 3.66 (q,J = 10.0 Hz, 2H), 1.24 (s, 3H). MS: m / z 247.9 (M + H+ ).step 3 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6-methoxy-6-methyl- 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method D Medium synthesis, resulting in the desired product (7.0 mg, yield: 73%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 6.80 (s, 1H), 4.15 (s, 3H), 4.01 (s, 2H), 2.75 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 8.4 Hz, 4H), 2.58 (overlap, 2H), 1.92-1.88 (m, 4H), 1.20 (s, 3H). MS: m / z 447.1 (M + H+ ).Examples 56 Shown belowRacemization - ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (3-methoxyazetidine Synthesis of 1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide sodium. step 1 N, N-dibenzyl-6- pendantoxy-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonium at room temperature To a stirred solution of amine (794 mg, 2.0 mmol) and azetidin-3-ol hydrochloride (440.0 mg, 4.0 mmol) in MeOH (30.0 mL) was added sodium triacetoxyborohydride (848.0 mg , 4.0 mmol). The mixture was then stirred at room temperature for 30 min. To the mixture was added sodium cyanotrihydroborate (252.0 mg, 4.0 mmol) and stirred at room temperature for 16 hr. The mixture was concentrated in vacuo. By silica gel column chromatography (CH2 Cl2 / MeOH = 5/1) purified residue to give a yellow solidRacemization - N, N-dibenzyl-6- (3-hydroxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine -3-sulfamethoxamine (340 mg, yield: 37%). MS: m / z 455.2 (M + H+ ).step 2 toRacemization - N, N-dibenzyl-6- (3-hydroxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine To a solution of -3-sulfamethoxamine (105 mg, 0.2 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 14.0 mg, 0.4 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. Then methyl iodide (39.0 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL).2 SO4 Dry and concentrate to dryness to give a yellow oilRacemization - N, N-dibenzyl-6- (3-methoxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-3-sulfamethoxamine (120 mg, crude). MS: m / z 469.1 (M + H+ ).step 3 toRacemization - N, N-dibenzyl-6- (3-methoxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] Oxazine-3-sulfamethoxamine (120 mg, 0.3 mmol) in CH2 Cl2 (3.0 mL) add concentrated H to the stirred solution2 SO4 (16 drops, 0.32 mL) and stirred at room temperature for 30 min. The reaction solution was concentrated. The residue was saturated with NaHCO3 Neutralize the solution. The solid was then filtered from the mixture and reversed-phase HPLC (MeCN / H2 O) Purify the filtrate to give a white solidRacemization - 6- (3-methoxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (52.0 mg, yield: 70%). MS: m / z 289.1 (M + H+ ).step 4 Racemization - ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (3-methoxyazetidine -1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium is as followsManufacturing method D Medium synthesis, resulting in the desired product (10.0 mg, yield: 11%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.85 (brs, 1H), 7.57 (s, 1H), 6.92 (s, 1H), 4.30-4.28 (m, 2H), 4.17-4.12 (m, 1H), 3.91-3.84 (m, 2H ), 3.52 (t,J = 7.2 Hz, 2H), 3.14 (s, 3H), 3.01-2.94 (m, 3H), 2.79 (t,J = 7.2 Hz, 4H), 2.62 (t,J = 7.2 Hz, 4H), 1.99-1.92 (m, 4H). MS: m / z 488.2 (M + H+ ).Examples 57 Shown below (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (3-methoxyaza (Cyclobut-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide and (S )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (3-methoxyaza Synthesis of cyclobut-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonamido) sulfonamide. step 1 Resolution by chiral prep-HPLCRacemization - 6- (3-methoxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (150 mg) to give a white solid (R ) -6- (3-methoxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonate Amidine (65 mg) and white solid (S ) -6- (3-methoxyazetidin-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonate Phenamine (60 mg).step 2 (R )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (3-methoxyaza Cyclobut-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium is as followsManufacturing method D Medium synthesis, resulting in the desired product (54.0 mg, yield: 48%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.37 (brs, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.13-4.08 (m, 3H), 3.96-3.92 (m, 1H), 3.79-3.76 (m, 1H ), 3.55-3.53 (m, 2H), 3.14 (s, 3H), 2.98-2.94 (m, 2H), 2.87 (br, 1H), 2.75 (t,J = 6.8 Hz, 4H), 2.66 (t,J = 6.8 Hz, 4H), 1.92-1.89 (m, 4H). MS: m / z 488.2 (M + H+ ). (S )-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- (3-methoxyaza Cyclobut-1-yl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium system using the same procedure preparation.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.39 (brs, 1H), 7.30 (s, 1H), 6.76 (s, 1H), 4.12-4.06 (m, 3H), 3.95-3.92 (m, 1H), 3.79-3.76 (m, 1H ), 3.55-3.52 (m, 2H), 3.14 (s, 3H), 2.98-2.92 (m, 2H), 2.88 (br, 1H), 2.75 (t,J = 7.2 Hz, 4H), 2.66 (t,J = 7.2 Hz, 4H), 1.95-1.87 (m, 4H). MS: m / z 488.2 (M + H+ ).Examples 58 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethane) -6,7-dihydro-4H- Synthesis of pyrazolo [5,1-c] [1,4] oxazine-2-sulfonamide. step 1 To a solution of 2-bromoethanol (3.8 g, 30.0 mmol) and DHP (2.5 g, 30.0 mmol) in DCM (50 mL) was added TsOH (380.0 mg, 2.2 mmol) in portions and the mixture was stirred at room temperature. 2 hr. The reaction was concentrated and purified by a silica gel column (PE / EA = 50/1) to give 2- (2-bromoethoxy) tetrahydro-2H-pyran (5.6 g, yield: 89%) as a colorless oil. ).1 H NMR (400 MHz, CDCl3 ): δ = 4.68 (t,J = 3.2 Hz, 1H), 4.05-3.99 (m, 1H), 3.92-3.86 (m, 1H), 3.80-3.74 (m, 1H), 3.54-3.49 (m, 3H), 1.85-1.71 (m, 3H ), 1.65-1.53 (m, 3H).step 2 To a solution of 3-nitro-1H-pyrazole-5-carboxylic acid (1.57 g, 10.0 mmol) in MeOH (20 mL) was added concentrated H2 SO4 (2.0 mL). The resulting mixture was stirred at 65 ° C overnight. The mixture was then concentrated in vacuo to give a residue, which was purified by a silica gel column (DCM / MeOH = 50/1) to give 3-nitro-1H-pyrazole-5-carboxylic acid as a yellow solid Methyl ester (1.42 g, yield: 83%).1 H NMR (400 MHz, DMSO-d 6 ):δ = 15.24 (brs, 1H), 7.54 (s, 1H), 3.90 (s, 3H).step 3 To a solution of 3-nitro-1H-pyrazole-5-carboxylic acid methyl ester (1.7 g, 10.0 mmol) in NMP (20 mL) was added 2- (2-bromoethoxy) tetrahydro-2H- Pyran (2.6 g, 13.0 mmol) followed by K2 CO3 (1.7 g, 13.0 mmol). The resulting mixture was stirred at 80 ° C for 16 hr. Then filter K2 CO3 . The filtrate was concentrated in vacuo to give a residue, which was purified by a silica gel column (PE / EA = 2/1) to give 3-nitro-1- (2-((tetrahydro- 2H-pyran-2-yl) oxy) ethyl) -1H-pyrazole-5-carboxylic acid methyl ester (2.8 g, yield: 94%).1 H NMR (400 MHz, CDCl3 ):δ = 7.39 (s, 1H), 4.92 (t,J = 7.2 Hz, 2H), 4.57 (s, 1H), 4.11-4.07 (m, 1H), 3.98 (overlapping, 1H), 3.96 (s, 3H), 3.84-3.80 (m, 1H), 3.64-3.60 ( m, 1H), 3.49-3.46 (m, 1H), 1.67-1.46 (m, 6H).step 4 To 3-nitro-1- (2-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazole-5-carboxylic acid methyl ester (2.5 g , 8.4 mmol) to a solution in anhydrous THF (50 mL) was added LiBH4 (6.3 mL, 2.0 M in THF). The resulting mixture was stirred from 0 ° C to room temperature for 3 hr. The reaction was then quenched by the addition of MeOH (4 mL). The mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column (PE / EA = 1/1) to give a yellow oil (3-nitro-1- (2-((quad Hydrogen-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazol-5-yl) methanol (2.2 g, yield: 96%).1 H NMR (300 MHz, CDCl3 ):δ = 6.88 (s, 1H), 4.69 (t,J = 6.3 Hz, 2H), 4.57-4.49 (m, 3H), 4.21-4.16 (m, 1H), 3.92-3.85 (m, 1H), 3.77-3.65 (m, 2H), 3.51-3.42 (m, 2H ), 1.72-1.48 (m, 6H).step 5 To (3-nitro-1- (2-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazol-5-yl) methanol (2.0 g , 7.5 mmol), pyridine (593 mg, 7.5 mmol) and perbromomethane (5.0 g, 15.0 mmol) in anhydrous Et2 To a stirred solution of O (30 mL) was added triphenylphosphine (3.9 g, 15.0 mmol). The resulting mixture was stirred from 0 ° C to room temperature for 3 hr. The reaction was stirred at room temperature for 16 hr. The solid was then filtered from the reaction and the solvent was concentrated to dryness in vacuo to produce a yellow gum, which was purified by a silica gel column (PE / EA = 1/1) to give 5- (bromomethyl) as a yellow oil. Yl) -3-nitro-1- (2-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazole (1.5 g, yield: 60%).1 H NMR (400 MHz, CDCl3 ):δ = 6.89 (s, 1H), 4.69 (t,J = 16.0 Hz, 2H), 4.57-4.48 (m, 3H), 4.16-4.10 (m, 1H), 3.84-3.77 (m, 1H), 3.64-3.57 (m, 1H), 3.48-3.43 (m, 1H ), 1.72-1.45 (m, 6H).step 6 : 5- (Bromomethyl) -3-nitro-1- (2-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-pyrazole (1.5 g, 4.5 mmol ) To a solution in THF (5 mL) was added concentrated HCl (1.0 mL) and the mixture was stirred at room temperature for 16 hr. The reaction was concentrated under reduced pressure. The residue was saturated with NaHCO3 The solution was neutralized and extracted with EA (60 mL). The organic layer was washed with water (50 mL) and brine (50 mL).2 SO4 Dry and concentrate to dryness in vacuo to give a yellow gum, which was purified by a silica gel column (PE / EA = 1/1) to give 2- (5- (bromomethyl) -3 as a yellow oil -Nitro-1H-pyrazol-1-yl) ethanol (1.0 g, yield: 91%).step 7 To a solution of 2- (5- (bromomethyl) -3-nitro-1H-pyrazol-1-yl) ethanol (1.4 g, 4.47 mmol) in anhydrous THF was added NaH (60%, 197 mg, 4.92 mmol). N at room temperature2 After stirring for 4 hr, the reaction was partitioned between water (50 mL) and EA (50 mL). The organic layer was washed with brine (50 mL),2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 4/1) to give 2-nitro-6,7-dihydro-4H-pyrazolo [5,1-c] [1, as a white solid 4] Oxazine (300 mg, yield: 40%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 6.88 (s, 1H), 4.82 (s, 2H), 4.23 (t,J = 4.8 Hz, 2H), 4.12 (t,J = 4.8 Hz, 2H).step 8 To a solution of 2-nitro-6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazine (300 mg, 1.78 mmol) in MeOH (10 mL) Pd / C (10% wet, 100 mg). Place the reaction at room temperature in H2 (1 atm) with stirring for 3 hr and filtered. The filtrate was concentrated to give 6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazin-2-amine (250 mg, yield: quantitative) as a yellow gum. MS: m / z 277.0 (M-56 + H+ ).1 H NMR (300 MHz, DMSO-d 6 ): δ = 5.20 (s, 1H), 4.63-4.55 (m, 4H), 3.98-3.94 (m, 2H), 3.79-3.75 (m, 2H).step 9 6,7-Dihydro-4H-pyrazolo [5,1-c] [1,4] oxazin-2-amine (250 mg, 1.8 mmol) in MeCN / H2 To a solution in O (12 mL / 1 mL) was added concentrated HCl (2.7 mL) and AcOH (1.1 mL). The mixture was then cooled to 0 ° C and NaNO was slowly added2 (149 mg, 2.2 mmol) in H2 O (1 mL). After stirring at 0 ° C for 30 min, CuCl was added2 (121 mg, 0.9 mmol) and CuCl (9 mg, 0.09 mmol). Then make SO2 Bubbling through the reaction solution for 10 min. The reaction was partitioned between water (50 mL) and EA (50 mL). The organic layer was washed with brine (40 mL) and2 SO4 Dry and concentrate to give crude 6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazine-2-sulfonaminium chloride, which was used directly in the next step.step 10 A solution of crude 6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazine-2-sulfonyl chloride (crude, about 1.8 mmol) in THF (15 mL) To this was added ammonia (5 mL). The mixture was stirred at 60 ° C for 1 hr. The reaction was concentrated, acidified with 2 N HCl to pH = 5 and by reverse phase HPLC (MeCN / H2 O) Purification to give 6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazine-2-sulfonamide (100 mg, yield: Steps 27%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.42 (s, 2H), 6.39 (s, 1H), 4.80 (s, 2H), 4.17-4.14 (m, 2H), 4.08 (t,J = 4.8 Hz, 2H).step 11 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro-4H-pyrazole And [5,1-c] [1,4] oxazine-2-sulfonamideManufacturing method A Synthesized to deliver the desired product as a white solid (60 mg, yield: 30%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.86 (brs, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.59 (s, 1H), 4.81 (s, 2H), 4.19 (t,J = 4.8 Hz, 2H), 4.10 (t,J = 4.8 Hz, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.97-1.94 (m, 4H). MS: m / z 403.0 (M + H+ ).Examples 59 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -3,4-dihydro-2H- Synthesis of imidazo [5,1-b] [1,3] oxazine-8-sulfonamide. step 1 To a solution of 3-bromo-1-propanol (4 g, 28.8 mmol) in DCM (50 mL) at 0 ° C was added TsOH (496 mg, 2.88 mmol) and 3,4-2H-dihydropyran (7.2 g, 86.2 mmol). The mixture was stirred at room temperature overnight. Pour the reaction mixture into H2 O (100 mL). The mixture was extracted with DCM (70 mL x 2). The combined extracts were washed with brine (100 mL),2 SO4 Dry and concentrate to dryness. The residue was purified by a silica gel column (PE) to give 2- (3-bromo-propoxy) -tetrahydro-pyran (838 mg, yield: 57%) as a red solid.1 H NMR (300 MHz, DMSO-d 6 ): δ = 4.60-4.56 (m, 1H), 3.77-3.72 (m, 2H), 3.61-3.56 (m, 2H), 3.47-3.42 (m, 2H), 2.07-2.03 (m, 2H), 1.70 -1.61 (m, 2H), 1.51-1.45 (m, 4H).step 2 Add 5-bromo-1H-imidazole (6.6 g, 44.9 mmol) to ClSO3 Solution in H (30 mL) at 180 ° C under N2 Stir under atmosphere for 2 hr. The reaction mixture was poured into ice water (70 mL) and filtered. Filter cake with H2 O (30 mL) was washed and dried to give 5-bromo-1H-imidazole-4-sulfosulfanyl chloride as a yellow solid (7 g, yield: 63%).step 3 To a solution of 5-bromo-1H-imidazole-4-sulfosulfanyl chloride (4 g, 16.3 mmol) in THF (50 mL) at room temperature was added TEA (4.5 mL, 32.6 mmol) and dibenzylamine ( 3.2 g, 16.3 mmol). After stirring at room temperature overnight, the reaction mixture was poured into H2 O (100 mL) and extracted with EA (50 mL x 2). The combined EA was washed with brine (50 mL),2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give 5-bromo-1H-imidazole-4-sulfonic acid dibenzylfluorenamine as a red solid (1.4 g, yield: 21%) .1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.96 (s, 1H), 7.25-7.19 (m, 6H), 7.12-7.05 (m, 4H), 4.36 (s, 4H).step 4 Add K to a solution of 5-bromo-1H-imidazole-4-sulfonic acid dibenzylphosphonium amine (1.4 g, 3.2 mmol) in DMF (20 mL) at room temperature.2 CO3 (883 mg, 6.4 mmol), 2- (3-bromo-propoxy) -tetrahydro-pyran (856 mg, 3.8 mmol) and the mixture was taken at 80 ° C using N2 Stir overnight. Silicone was added to the reaction mixture and concentrated to dryness. The residue was purified by a silica gel column (PE / EA = 3/1 to 1/1) to give 5-bromo-1- [3- (tetrahydro-pyran-2-yloxy)-as a red oil Propyl] -1H-imidazole-4-sulfonic acid dibenzylamidamine (1.6 g, yield: 69%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 8.08 (s, 1H), 7.23-7.20 (m, 6H), 7.13-7.10 (m, 4H), 4.55-4.52 (m, 1H), 4.36 (s, 4H), 4.12 (t,J = 6.9 Hz, 2H), 3.72-3.64 (m, 2H), 3.40-3.30 (m, 2H), 2.02-1.95 (m, 2H), 1.80-1.59 (m, 2H), 1.50-1.40 (m, 4H ).step 5 Dibromo-1- [3- (tetrahydro-pyran-2-yloxy) -propyl] -1H-imidazole-4-sulfonic acid dibenzylamine (1.6 g, 3.0 at room temperature) To a solution in THF (10 mL) was added MeOH (5 mL), aq. HCl (6 mL, 6 N) and it was stirred at room temperature for 1 hr. Pour the reaction mixture into H2 O (50 mL) and saturated NaHCO3 Neutralize to pH = 7. The resulting mixture was extracted with EA (30 mL x 2). The combined EA was washed with brine (50 mL),2 SO4 Dry and concentrate to give 5-bromo-1- (3-hydroxy-propyl) -1H-imidazole-4-sulfonic acid dibenzylfluorenamine (1.4 g, crude) as a red oil.step 6 To a solution of 5-bromo-1- (3-hydroxy-propyl) -1H-imidazole-4-sulfonic acid dibenzylamidine (1.4 g, 3.0 mmol) in DMF (20 mL) was added NaH (60 %, 145 mg, 3.6 mmol) and the mixture at 80 ° C under N2 Stir for 4 hr. Pour the reaction mixture into H2 O (100 mL) and extracted with EA (50 mL x 3). Use merged EA layer with H2 O (60 mL x 2) washed with Na2 SO4 Dry and concentrate to dryness. By prep-HPLC (NH4 HCO3 ) The residue was purified to give 3,4-dihydro-2H-imidazo [5,1-b] [1,3] oxazine-8-sulfonic acid dibenzylamine (176 mg, product Rate: 16%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 7.23-7.18 (m, 6H), 7.15-7.12 (m, 4H), 4.34 (t,J = 5.1 Hz, 2H), 4.26 (s, 4H), 4.08 (t,J = 6.3 Hz, 2H), 2.10-2.06 (m, 2H).step 7 To 3,4-dihydro-2H-imidazo [5,1-b] [1,3] oxazine-8-dibenzylsulfonamide (170 mg, 0.44 mmol) in DCM ( 3 mL)2 SO4 (12 drops) and the mixture was stirred at room temperature for 30 minutes. Pour the reaction mixture into saturated NaHCO3 (20 mL) and then concentrated to remove DCM. The resulting solution was neutralized to pH = 7 and filtered. By reversed-phase HPLC (20% H2 MeCN in O) purified the filtrate to give 3,4-dihydro-2H-imidazo [5,1-b] [1,3] oxazine-8-sulfonamide (60 mg, product Rate: 62%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.32 (s, 1H), 6.87 (s, 2H), 4.33 (t,J = 5.7 Hz, 2H), 4.07 (t,J = 6.3 Hz, 2H), 2.09-2.05 (m, 2H).step 8 N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -3,4-dihydro-2H-imidazo [5,1-b] [1,3] oxazine-8-sulfonamideManufacturing method E Synthesized in to deliver the desired product (8 mg, yield: 8%) as a white solid.1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.98 (s, 1H), 7.40 (s, 1H), 6.91 (s, 1H), 4.33 (t,J = 2.4 Hz, 2H), 4.06 (t,J = 2.4 Hz, 2H), 2.80 (t,J = 3.0 Hz, 4H), 2.60 (t,J = 2.4 Hz, 4H), 2.07-2.05 (m, 2H), 1.98-1.92 (m, 4H). MS: m / z 403.1 (M + H+ ).Examples 60 Shown belowN -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadiene -4-yl) aminomethylamido) -4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Synthesis of pyrazine-2-sulfonamide. step 1 5-nitro-1H -Pyrazole-3-carboxylic acid methyl ester (100 mg, 0.58 mmol) in DMF (10 mL) was added with (2-bromoethyl) aminocarboxylic acid third butyl ester (197 mg, 0.88 mmol) And K2 CO3 (240 mg, 1.74 mmol). The reaction mixture was then stirred at 80 ° C for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 3/1) to give 1- (2-((third butoxycarbonyl) amino) ethyl) -3-nitro as a yellow solid -1H -Methyl pyrazole-5-carboxylate (166 mg, 80%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.57 (s, 1H), 6.96 (t,J = 6.0 Hz, 1H), 4.60 (d,J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.41-3.36 (m, 2H), 1.26 (s, 9H).step 2 To 1- (2-((third butoxycarbonyl) amino) ethyl) -3-nitro-1H -To a solution of pyrazole-5-carboxylic acid methyl ester (166 mg, 0.46 mmol) in dioxane (5 mL) was added HCl (1.15 mL, 4.6 mmol, 4 M in dioxane). The reaction mixture was then stirred at room temperature for 6 hr. The reaction mixture was concentrated in vacuo. Add residue to DMF (10 mL) and K2 CO3 (127 mg, 0.92 mmol). The reaction mixture was stirred at 80 ° C overnight and monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 50/1 to 10/1) to give 2-nitro-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (65 mg, 68%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.61 (s, 1H), 7.43 (s, 1H), 4.46 (t,J = 6.0 Hz, 2H), 3.72-3.65 (m, 2H).step 3 2-nitro-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (1.2 g, 6.6 mmol) in EtOH (30 mL) was added with iron powder (1.8 g, 33.0 mmol), NH4 Cl (1.76 g, 33.0 mmol) and H2 O (10 mL). The reaction mixture was heated at 80 ° C under N2 Stir overnight and monitor by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10/1) to give 2-amino-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (0.76 g, 76%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.01 (s, 1H), 5.80 (s, 1H), 4.88 (s, 2H), 3.98 (t,J = 5.6 Hz, 2H), 3.54-3.45 (m, 2H).step 4 Add CuCl (0.204 g, 2.1 mmol) to H under vigorous stirring at 0 ° C.2 Add SOCl dropwise to the suspension in O (265 mL)2 (44.85 mL, 0.618 mol). The solution was stirred at room temperature overnight, resulting in a pale yellow solution. Separately, 2-amino-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (0.62 g, 4.1 mmol) in concentrated HCl (4 mL) was added dropwise NaNO2 (0.33 g. 4.8 mmol) in H2 O (2 mL). The resulting dark orange solution was stirred at -10 ° C for 30 minutes, and then added to the copper (I) chloride solution (10.6 mL) from the first step at -5 ° C over 5 minutes. The reaction was stirred at -5 ° C for 1 hr and extracted with EA (10 mL × 3). The organic layer was concentrated in vacuo to give a yellow solid. This solid was dissolved in THF (20 mL), and then NH was added dropwise at 0 ° C.3 (10 mL, 28% wt). The reaction was stirred at 0 ° C for 2 hr and then concentrated in vacuo. The resulting solid was purified by silica gel column chromatography (DCM / MeOH = 10/1) to give 4-sideoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine-2-sulfamethoxamine (0.2 g, 23%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.46 (s, 1H), 7.59 (s, 2H), 6.94 (s, 1H), 4.39 (t,J = 5.2 Hz, 2H), 3.70-3.63 (m, 2H).step 5 N -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadiene -4-yl) aminomethylamido) -4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine-2-sulfamethoxamineManufacturing method F Synthesized in to deliver the desired product (8.3 mg, 4.3%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.37 (s, 1H), 7.81 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 6.85 (s, 1H), 4.33 (t,J = 6.0 Hz, 2H), 3.65-3.61 (m, 2H), 2.76 (t,J = 7.2 Hz, 4H), 2.63 (t,J = 6.8 Hz, 4H), 1.96-1.88 (m, 4H). MS: m / z 414.1 (M-H+ ).Examples 61 Shown belowN -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) aminomethyl) -5-methyl-4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Synthesis of pyrazine-2-sulfonamide. step 1 To 5-nitro-1 at -5 ° CH -Soluble solution of pyrazole-3-carboxylic acid (5.0 g, 31.8 mmol) and 2- (methylamino) ethanol (3.58 g, 47.7 mmol) in DCM (50 mL) was added dropwise.2 (11.5 mL, 159 mmmol) and DMF (4 drops) for 10 min. The reaction mixture was then stirred at 50 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was added to DMF (50 mL) and TEA (13.3 mL, 95.4 mmol). The reaction was then stirred at 60 ° C overnight. After removing the solvent in vacuo, the residue was purified by silica gel column chromatography (DCM / MeOH = 50/1 to 10/1) to give 5-methyl-2-nitro-6,7 as a yellow solid -Dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (4.66 g, 75%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.42 (s, 1H), 4.53 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.8 Hz, 2H), 3.03 (s, 3H).step 2 5-methyl-2-nitro-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (700 mg, 3.6 mmol) in EtOH (20 mL) was added with iron powder (1.0 g, 17.9 mmol), NH4 Cl (0.96 g, 17.9 mmol) and H2 O (7 mL). The reaction mixture was heated at 80 ° C under N2 Stir under atmosphere overnight and monitor by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM / MeOH = 50/1 to 10/1) to produce 2-amino-5-methyl-6,7-dihydropyrazolo [1 , 5-a ] Pyrazine-4 (5H ) -Ketone (0.44 g, 73%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 5.80 (s, 1H), 4.85 (brs, 2H), 4.08 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.4 Hz, 2H), 2.95 (s, 3H).step 3 Add CuCl (0.204 g, 2.1 mmol) to H at -5 ° C with vigorous stirring.2 Add SOCl dropwise to the suspension in O (265 mL)2 (44.85 mL, 0.618 mol). The solution was stirred at room temperature overnight, resulting in a pale yellow solution. Separately, 2-amino-5-methyl-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (100 mg, 0.6 mmol) in concentrated HCl (0.97 mL)2 (50 mg, 0.72 mmol) in H2 O (2 mL). The resulting dark orange solution was stirred at -10 ° C for 30 minutes at -5 ° C for 30 minutes and then added to the above copper (I) chloride solution (1.6 mL). The reaction was stirred at -5 ° C for 1 hr and extracted with EA (10 mL × 3). The organic layer was concentrated in vacuo to give a yellow solid. To this solid was added THF (5 mL), and then NH was added dropwise at -5 ° C.3 (3 mL, 28% wt). The reaction was stirred at 0 ° C for 2 hr, and then concentrated in vacuo. The obtained solid was purified by silica gel column chromatography (DCM / MeOH = 10/1) to give 5-methyl-4- pendantoxy-4,5,6,7-tetrahydropyrazolo [ 1,5-a ] Pyrazine-2-sulfamethoxamine (42 mg, 30%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.60 (s, 2H), 6.93 (s, 1H), 4.46 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.4 Hz, 2H), 3.01 (s, 3H).step 4 N -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) aminomethyl) -5-methyl-4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine-2-sulfamethoxamineManufacturing method E Synthesized in to deliver the desired product (21.8 mg, 12%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.70 (s, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 4.39 (t,J = 6.0 Hz, 2H), 3.78 (t,J = 6.4 Hz, 2H), 3.34 (s, 3H), 2.76 (t,J = 7.2 Hz, 4H), 2.64 (t,J = 7.2 Hz, 4H), 1.96-1.86 (m, 4H). MS: m / z 430.0 (M + H+ ).Examples 62 Shown belowN -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) aminomethyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a Synthesis of pyrazine-3-sulfonamide. step 1 4-nitro-1H -To a solution of pyrazole-5-carboxylic acid (1.0 g, 6.4 mmol) in MeOH (30 mL) was added TsOH (52 mg, 0.3 mmol). The reaction mixture was then stirred at 65 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 40/1 ~ 10/1) to give 4-nitro-1 as a white solidH -Methyl pyrazole-5-carboxylate (1.0 g, 91%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.90 (s, 1H), 3.88 (s, 3H).step 2 4-nitro-1H -Pyrazole-5-formate (3.0 g, 17.5 mmol) in MeOH (100 mL) was added (Boc)2 O (4.2 g, 19.25 mmol) and Pd / C (300 mg, 10% wt). The reaction mixture was then2 Stir under atmosphere overnight and monitor by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 2/1 ~ 1/1) to give 4-((third butoxycarbonyl) amino) -1 as a white solidH -Methyl pyrazole-5-carboxylate (2.52 g, 60%).step 3 4-((Third butoxycarbonyl) amino) -1H -To a solution of pyrazole-5-carboxylic acid methyl ester (4.2 g, 17.4 mmol) in DMF (50 mL) was added (2-bromoethyl) aminocarboxylic acid third butyl ester (5.8 g, 26.1 mmol) And K2 CO3 (7.2 g, 52.2 mmol). The reaction mixture was then stirred at 80 ° C overnight and monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 3/1) to give 4-((third butoxycarbonyl) amino) -1- (2-((third (Oxycarbonyl) amino) ethyl) -1H -Methyl pyrazole-5-carboxylic acid ester (1.26 g, 19%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.16 (s, 1H), 7.80 (s, 1H), 6.81 (t,J = 6.8 Hz, 1H), 4.40 (t,J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.29- 3.22 (m, 2H), 1.46 (s, 9H), 1.33 (s, 9H).step 4 4-((Third butoxycarbonyl) amino) -1- (2-((third butoxycarbonyl) amino) ethyl) -1H -Pyrazole-5-carboxylic acid methyl ester (1.26 g, 3.3 mmol) in DCM (20 mL) was added with CF3 CO2 H (2.4 mL, 33 mmol). The reaction mixture was then stirred at room temperature overnight and monitored by LCMS. The reaction mixture was concentrated in vacuo. Add residue to DMF (20 mL) and K2 CO3 (1.36 mg, 9.9 mmol). The reaction mixture was stirred at 80 ° C overnight and monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 20/1 ~ 10/1) to give 3-amino-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (354 mg, 71%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.75 (brs, 1H), 7.00 (s, 1H), 4.68 (brs, 2H), 4.08 (d,J = 5.6 Hz, 2H), 3.55-3.47 (m, 2H).step 5 Add CuCl (0.204 g, 2.1 mmol) to H under vigorous stirring at 0 ° C.2 Add SOCl dropwise to the suspension in O (265 mL)2 (44.85 mL, 0.618 mol). The solution was stirred at room temperature overnight, resulting in a pale yellow solution. Separately, 3-amino-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (155 mg, 1.02 mmol) in concentrated HCl (1 mL) was added dropwise with NaNO2 (84.4 mg. 1.23 mmol) in H2 O (2 mL). The obtained dark orange solution was stirred at -10 ° C for 30 minutes and then added to the above-mentioned copper (I) chloride solution (2.65 mL) at -5 ° C over 5 minutes. The reaction was stirred at -5 ° C for 1 hr and then extracted with EA (10 mL × 3). The organic layer was concentrated in vacuo to give a yellow solid. This solid was dissolved in THF (5 mL), and then NH was added dropwise at 0 ° C.3 (4 mL, 28% wt). The reaction was stirred at 0 ° C for 2 hr and then concentrated in vacuo. The obtained solid was purified by prep-TLC (DCM / MeOH = 10/1) to give 4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine-3-sulfamethoxamine (5 mg, 2.2%).step 6 N -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) aminomethyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine-3-sulfonamideManufacturing method E Synthesized in to deliver the desired product (1.1 mg, 5.8%) as a yellow solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.64 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 6.87 (s, 1H), 4.38 (d,J = 5.6 Hz, 2H), 3.65-3.59 (m, 2H), 2.77 (t,J = 6.8 Hz, 4H), 2.57 (t,J = 7.2 Hz, 4H), 1.97-1.87 (m, 4H). MS: m / z 416.1 (M + H+ ).Examples 63 Shown belowN -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) aminomethyl) -5-methyl-4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a Synthesis of pyrazine-3-sulfonamide. step 1 4-nitro-1 at -5 ° CH -Soluble to a solution of pyrazole-5-carboxylic acid (1.0 g, 6.4 mmol) and 2- (methylamino) ethanol (0.55 g, 7.3 mmol) in toluene (5 mL)2 (20 mL) and DMF (3 drops) for 10 min. The reaction mixture was then stirred at 80 ° C. overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in DMF (20 mL) and TEA (2.7 mL, 19.3 mmol). The reaction was then stirred at 60 ° C. overnight and monitored by LCMS. After removing the solvent in vacuum, the residue was purified by silica gel column chromatography (PE / EA = 3/1 ~ 1/1) to give 5-methyl-3-nitro-6,7 as a yellow solid -Dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (0.7 g, 56%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.34 (s, 1H), 4.47 (t,J = 5.6 Hz, 2H), 3.85 (t,J = 6.4 Hz, 2H), 3.05 (s, 3H).step 2 5-methyl-3-nitro-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (3.52 g, 18 mmol) in EtOH (75 mL) was added with iron powder (5.04 g, 90 mmol), NH4 Cl (4.82 g, 90 mmol) and H2 O (25 mL). The reaction mixture was heated at 80 ° C under N2 Stir under atmosphere overnight and monitor by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10/1) to give 3-amino-5-methyl-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (2.58 g, 86%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.01 (s, 1H), 4.76 (s, 2H), 4.16 (t,J = 6.0 Hz, 2H), 3.66 (t,J = 6.4 Hz, 2H), 2.94 (s, 3H).step 3 Add SOCl dropwise to water (70 mL) at -5 ° C2 (20 mL). The solution was stirred at 5 ° C for 1 hr and at room temperature for 1 hr. CuCl (0.16 g) was added, resulting in a yellow solution. It was stirred at room temperature for 5 min and then cooled to -10 ° C. Separately, 3-amino-5-methyl-6,7-dihydropyrazolo [1,5-a ] Pyrazine-4 (5H ) -Ketone (358 mg, 2.2 mmol) in concentrated HCl (2.0 mL) was added dropwise NaNO2 (180 mg, 2.62 mmol) in H2 O (1.6 mL). The obtained dark orange solution was stirred at -10 ° C for 30 minutes and then added to the above-mentioned copper (I) chloride solution (5.7 mL) at -5 ° C over 5 minutes. The reaction was stirred at -5 ° C for 1 hr and then extracted with EA (5 mL x 3). The organic layer was concentrated in vacuo to give a yellow solid. This solid was dissolved in THF (5 mL), and then NH was added dropwise at -5 ° C.3 (3 mL, 28% wt). The reaction was stirred at 0 ° C for 2 hr and then concentrated in vacuo. The obtained solid was purified by prep-TLC (DCM / MeOH = 10/1) to give 5-methyl-4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1, as a yellow solid 5-a ] Pyrazine-3-sulfazone (30 mg, 6%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (s, 1H), 7.18 (s, 2H), 4.48 (t,J = 6.0 Hz, 2H), 3.87 (t,J = 6.4 Hz, 2H), 3.06 (s, 3H).step 4 NaH (6.24 mg, 0.156 mmol, 60% dispersion in paraffin liquid) in DMSO (2 mL) was stirred at 70 ° C for 30 min. To a solution of NaH in DMSO (2 mL) at -5 ° C was then added 5-methyl-4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine-3-sulfamethoxamine (30 mg, 0.13 mmol) and stirred at -5 ° C for 30 min. Separately, at -5 ° C towards 1,2,3,5,6,7-hexahydro-s- To a solution of dicyclopentadienacene-4-amine (24.8 mg, 0.14 mmol) in THF (5 mL) was added triphosgene (15.4 mg, 0.052 mmol) and TEA (0.1 mL). The reaction mixture was then stirred at -5 ° C for 30 min and monitored by TCL. This reaction was filtered and the filtrate was added at (-5a ] Pyrazine-3-yl) sulfofluorenyl) sulfonamide sodium in the above suspension. The reaction was stirred at room temperature overnight and monitored by LC-MS. This reaction was then treated with saturated NH4 Aqueous Cl (5 mL x 3) was washed. Pass the organic layer over anhydrous Na2 SO4 Dry and concentrate in vacuo. The residue was purified by prep-HPLC to give a white solidN -((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) aminomethyl) -5-methyl-4- pendantoxy-4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine-3-sulfamethoxamine (12.8 mg, 25%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.27 (brs, 1H), 7.91 (s, 1H), 6.90 (s, 1H), 4.47 (t,J = 5.6 Hz, 2H), 3.83 (t,J = 6.0 Hz, 2H), 3.06 (s, 3H), 2.77 (t,J = 6.8 Hz, 4H), 2.55 (t,J = 7.6 Hz, 4H), 1.99-1.88 (m, 4H). MS: m / z 430.1 (M + H+ ).Examples 64 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -4,5,6,7-tetra Synthesis of Hydropyrazolo [1,5-a] pyrimidine-3-sulfonamide. step 1 To a solution of 1H-pyrazole-5-amine (9.8 g, 0.1 mol) and TEA (36.0 g, 0.3 mmol) in 1,4-dioxane (200 mL) was added 1,3-dibromopropane ( 26.3 g, 0.1 mmol). After stirring at 110 ° C for 5 hr, the reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by a silica gel column (DCM / MeOH = 100/1) to give 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine (5.3 g, yield) as a white solid. : 36%).1 H NMR (300 MHz, CDCl3 ): δ = 7.18 (s, 1H), 5.26 (s, 1H), 4.22-4.00 (m, 3H), 3.26-3.22 (m, 2H), 2.11-2.03 (m, 2H).step 2 To a solution of 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine (3.0 g, 24.4 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 1.5 g, 36.6 mmol). Place the reaction at room temperature under N2 Stir for 1 hr. Then add Boc2 O (8.0 g, 36.6 mmol) and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water (60 mL) and extracted with EA (50 mL x 2). The organic layer was washed with water (50 mL) and brine (50 mL).2 SO4 Dry and concentrate. The residue was purified by a silica gel column (DCM / MeOH = 100/1) to give 6,7-dihydropyrazolo [1,5-a] pyrimidine-4 (5H) -formic acid tert-butyl as a white solid. Ester (4.4 g, yield: 81%).1 H NMR (300 MHz, CDCl3 ): δ = 7.37 (s, 1H), 6.28 (s, 1H), 4.21-4.16 (m, 2H), 3.86-3.80 (m, 2H), 2.20-2.15 (m, 2H), 1.57 (s, 9H ). MS: m / z 224.4 (M + H+ ).step 3 A solution of 6,7-dihydropyrazolo [1,5-a] pyrimidine-4 (5H) -formic acid third butyl ester (4.4 g, 19.6 mmol) in MeCN (20 mL) at 0 ° C NBS (4.2 g, 23.5 mmol) was added in portions and the reaction was stirred at room temperature for 16 hr. The reaction mixture was poured into water (40 mL) and extracted with EA (40 mL x 2). The organic layer was washed with water (40 mL) and brine (40 mL).2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give 3-bromo-6,7-dihydropyrazolo [1,5-a] pyrimidine-4 (5H)-as a yellow solid. Third butyl formate (4.1 g, yield: 69%). MS: m / z 304.3 (M + H+ ).step 4 3-((2,4,6-trichlorophenoxy) sulfonyl) -6,7-dihydropyrazolo [1,5-a] pyrimidine-4 (5H) -carboxylic acid third butyl ester Department of useManufacturing method B Synthesized to give a yellow oily product which was used in the next step without purification.step 5 3-((2,4,6-trichlorophenoxy) sulfonyl) -6,7-dihydropyrazolo [1,5-a] pyrimidine-4 (5H) -formic acid tert-butyl Esters (crude, about 1.85 mmol), NH4 A mixture of OH (5 mL) and THF (20 mL) was stirred at 60 ° C for 12 hr. The reaction was concentrated under reduced pressure. The remaining solution was acidified with aq. HCl (1 N) to pH = 5 and partitioned between EA (60 mL) and water (60 mL). The organic layer was washed with water (60 mL), brine (60 mL), and2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 1/1) to give 3-aminesulfonyl-6,7-dihydropyrazolo [1,5-a] pyrimidine-4 ( 5H) -Thirty butyl formate (100 mg, yield: 18% over 2 steps).1 H NMR (300 MHz, CDCl3 ): δ = 7.80 (s, 1H), 5.54 (brs, 2H), 4.23 (t,J = 6.3 Hz, 2H), 3.96 (t,J = 6.0 Hz, 2H), 2.23-2.19 (m, 2H), 1.57 (s, 9H). MS: m / z 303.1 (M + H+ ).step 6 To 1, 2, 3, 5, 6, 7-hexahydro-s-dicyclopentadienyl-4-ylamine (68.7 mg, 0.397 mmol) and TEA (0.16 mL, 1.2 mmol) in THF (5 To the solution in mL) was added triphosgene (47.2 mg, 0.16 mmol). The mixture was stirred at room temperature for 20 minutes. In another round-bottomed flask, 3-aminosulfonyl-6,7-dihydropyrazolo [1,5-a] pyrimidin-4 (5H) -carboxylic acid third butyl ester (120 mg, 0.397 mmol ) To a solution in THF (5 ml) was added MeONa (23.6 mg, 0.436 mmol) and the mixture was stirred at room temperature for 20 minutes. The prepared 4-isocyanato-1,2,3,5,6,7-hexahydro-s-dicyclopentadiene acene was filtered to remove the resulting precipitate and the filtrate was added to a salt containing sulfonamide In another flask. After 30 minutes, the reaction was quenched with the addition of water (30 mL). The aqueous phase was extracted with EA (20 mL) and filtered. The filtrate was acidified to pH = 3 ~ 4, and it was extracted with EA (20 mLx2) to produce 3- (N-((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) carbamoyl) sulfamoyl) -6,7-dihydropyrazolo [1,5-a] pyrimidin-4 (5H) -formic acid tert-butyl Ester (32 mg, yield: 16%).step 7 To 3- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamido) aminesulfonyl) -6, TFA (1 mL) was added to a solution of 7-dihydropyrazolo [1,5-a] pyrimidine-4 (5H) -third butyl formate (32 mg, 0.064 mmol) in DCM (2 mL) And the mixture solution was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS, and the reaction mixture was concentrated to dryness in vacuo. The residue was purified by prep-HPLC (NH3 · H2O) to give N-(((1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4- Yl) aminomethylamidino) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-sulfonamide (11.6 mg, yield: 45%).1 H NMR (300 MHz, DMSO-d 6 ): δ = 8.01 (s, 1H), 7.39 (s, 1H), 6.92 (s, 1H), 6.42 (s, 1H), 3.96 (t,J = 5.6 Hz, 2H), 3.25-3.23 (m, 2H), 2.79 (t,J = 7.6 Hz, 4H), 2.60 (t,J = 7.2 Hz, 4H), 1.97-1.91 (m, 6H). MS: m / z 402.0 (M + H+ ).Examples 65 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -4,5,6,7-tetra Synthesis of Hydropyrazolo [1,5-a] pyrazine-2-sulfamethoxamine trifluoroacetic acid. step 1 To a solution of 3-nitro-1H-pyrazole-5-carboxylic acid (1.57 g, 10.0 mmol) in MeOH (20 mL) was added concentrated H2 SO4 (2.0 mL). The resulting mixture was stirred at 65 ° C overnight. The mixture was then concentrated in vacuo to give a residue, which was purified by a silica gel column (DCM / MeOH = 50/1) to give 3-nitro-1H-pyrazole-5-carboxylic acid as a yellow solid Methyl ester (1.42 g, yield: 83%).1 H NMR (400 MHz, DMSO-d 6 ):δ = 15.24 (brs, 1H), 7.54 (s, 1H), 3.90 (s, 3H).step 2 To a solution of 3-nitro-1H-pyrazole-5-carboxylic acid methyl ester (342 mg, 2.0 mmol) in acetone (40 mL) was added 1,2-dibromoethane (412 mg, 2.2 mmol) And add K2 CO3 (828 mg, 6.0 mmol). The resulting mixture was stirred at reflux for 2 hr. Then filter K2 CO3 . The filtrate was concentrated in vacuo to give a residue, which was purified by a silica gel column (DCM / MeOH = 50/1) to give 1- (2-bromoethyl) -3-nitro- as a yellow solid 1H -Pyrazole-5-carboxylic acid methyl ester (430 mg, yield: 77%).1 H NMR (400 MHz, CDCl3 ):δ = 7.42 (s, 1H), 5.08 (t,J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.78 (t,J = 6.4 Hz, 2H).step 3 To 1- (2-bromoethyl) -3-nitro-1 at 0 ° CH -Pyrazole-5-formate (278 mg, 1.0 mmol) in anhydrous THF (20 mL) was added with LiBH4 (2 mL, 2.0 M in THF). The resulting mixture was stirred from 0 ° C to room temperature for 3 hr. The reaction was then quenched by the addition of MeOH (4 mL). The mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column (DCM / MeOH = 100/1) to give (1- (2-bromoethyl) -3-nitrate as a white solid Base-1H -Pyrazol-5-yl) methanol (122 mg, yield: 49%).1 H NMR (400 MHz, DMSO-d 6 ):δ = 6.99 (s, 1H), 5.69 (t,J = 5.6 Hz, 1H), 4.66 (t,J = 6.0 Hz, 2H), 4.61 (d,J = 5.6 Hz, 2H), 3.91 (t,J = 6.4 Hz, 2H).step 4 [2- (2-Bromo-ethyl) -5-nitro-2H-pyrazol-3-yl] -methanol (3.0 g, 12.0 mmol), PBr3 (4.9 g, 18.0 mmol) and CH2 Cl2 (50 mL) of the mixture was stirred at 45 ° C for 3 hr. Saturate the reaction with saturated NaHCO3 Neutralize and use CH2 Cl2 (60 mL) was extracted and the combined organic layers were washed with brine (50 mL),2 SO4 Dry, filter, and concentrate to dryness in vacuo to give 1- (2-bromo-ethyl) -5-bromomethyl-3-nitro-1H-pyrazole (2.2 g, yield: 58%).1 H NMR (300 MHz, CDCl3 ): δ = 6.93 (s, 1H), 4.63 (t,J = 3.8 Hz, 2H), 4.53 (s, 2H), 3.86 (t,J = 4.2 Hz, 2H).step 5 Add 1- (2-bromo-ethyl) -5-bromomethyl-3-nitro-1H-pyrazole (1.5 g, 4.8 mmol), NH3 . H2 A mixture of O (8 mL) and MeOH (10 mL) was stirred in a sealed tube at 50 ° C for 16 hr. The reaction mixture was concentrated to dryness in vacuo to give 2-nitro-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyrazine (700 mg, yield: 87%). MS: m / z 169.0 (M + H+ ).step 6 Add 2-nitro-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyrazine (700 mg, 4.2 mmol), CbzCl (700 mg, 4.2 mmol), K2 CO3 (1.2 g, 8.4 mmol) and CH3 The mixture in CN (20 mL) was stirred at room temperature for 16 hr. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by a silica gel column (PE / EA = 5/1 to 1/1) to give 2-nitro-6,7-dihydro-4H-pyrazolo [1,5-a as a yellow solid ] Pyrazine-5-carboxylic acid benzyl ester (900 mg, yield: 69%).step 7 Benzyl 2-nitro-6,7-dihydro-4H-pyrazolo [1,5-a] pyrazine-5-carboxylate (710 mg, 2.4 mmol), Fe (658 mg, 11.8 mmol) , NH4 Cl (637 mg, 11.8 mmol), H2 A mixture of O (10 mL) and EtOH (20 mL) was stirred at 80 ° C for 16 hr. The reaction mixture was filtered through a celite pad and washed with CH2 Cl2 (30 mL). The filtrate solution was concentrated to dryness to give benzyl 2-amino-6,7-dihydro-4H-pyrazolo [1,5-a] pyrazine-5-carboxylate (639 mg, product Rate: 98%).step 8 Benzyl 2-amino-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -formate (639 mg, 2.4 mmol) in MeCN (8 mL at 0 ° C) Use H in solution2 Concentrated HCl (3.0 mL) in O (1.2 mL) followed by NaNO2 (198 mg, 2.9 mmol) in H2 O (0.9 mL). The solution was stirred at 0 ° C for 45 min. To the above mixture was added AcOH (1.2 mL), CuCl,2 (162 mg, 1.2 mmol) and CuCl (12 mg, 0.12 mmol) and SO at 0 ° C2 The gas was purged for 25 min. After stirring at 0 ° C for 1 hr, the reaction mixture was poured into ice water (100 mL) and extracted with EA (40 mL x 3). Pass the combined organic layers over Na2 SO4 Dry, filter and evaporate in vacuo to give 2- (chlorosulfonyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -formic acid benzyl as a yellow oil Ester (crude). This material was used in the next step without further purification.step 9 A solution of 2- (chlorosulfanyl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -benzyl formate (crude) in THF (6 mL) Add NH3 . H2 O (3 mL). After stirring at room temperature for 20 min, the reaction mixture was concentrated, diluted with MeOH (5 mL) and acidified with aq. HCl (1 N) to pH = 5. By reversed-phase HPLC (0% -50% H2 MeCN in O) purified the resulting solution to give 2-aminesulfonamido-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -benzyl formate as a white solid ( 122 mg, yield: 15%, two steps). MS: m / z 337.0 (M + H+ ).step 10 2-Aminosulfonyl-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -benzyl formate (102 mg, 0.3 mmoL),2 A solution of O (73 mg, 0.33 mmoL) and Pd / C (20 mg) in MeOH (10 mL) was stirred at room temperature under a hydrogen atmosphere (50 psi) for 16 hr. The reaction mixture was filtered and concentrated to dryness in vacuo. With silicone tubing (CH2 Cl2 / MeOH = 40/1) The residue was purified to give 2-aminesulfonyl-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -formic acid as a yellow solid. Butyl ester (106 mg, yield: 96%). MS: m / z 303.0 (M + H+ ).step 11 2- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylsulfanyl) aminesulfonyl) -6,7 -Dihydropyrazolo [1,5-a] pyrazine-5 (4H) -formic acid third butyl ester such asManufacturing method F Synthesized in to deliver the desired product (108 mg, crude) as a yellow solid. MS: m / z 502.1 (M + H+ ).step 12 : To 2- (N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethylamido) aminesulfonyl) -6, 7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylic acid third butyl ester (68 mg, crude) in CH2 Cl2 (1 mL) was added to TFA (0.5 mL) and the mixture was stirred at room temperature for 30 min. By reversed-phase HPLC (0% -50% H2 MeCN in O) purifies the resulting solution to give N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-yl) amine formamidine as a white solid ) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfamethoxamine TFA salt (7.9 mg, 15%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.01 (s, 1H), 6.93 (s, 1H), 6.50 (s, 1H), 4.05 (t,J = 4.8 Hz, 2H), 3.93 (s, 2H), 3.17 (t,J = 5.2 Hz, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.61 (t,J = 7.6 Hz, 4H), 1.99-1.94 (m, 4H). MS: m / z 401.9 (M + H+ ).Examples 66 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -5-methyl-4,5, Synthesis of 6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide. step 1 3-Aminosulfino-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylic acid third butyl ester (60 mg, 0.2 mmol) in CH2 Cl2 (1 mL) was added to TFA (2 mL) and the mixture was stirred at room temperature for 30 min. By reversed-phase HPLC (0%-50% H2 MeCN in O) purified the resulting solution to yield 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide TFA salt (50 mg, crude) as a brown solid . MS: m / z 202.9 (M + H+ ).step 2 Add formaldehyde to a stirred solution of 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfamethoxamine TFA salt (45 mg, crude) in MeOH (10 mL) (40 mg, 1.3 mmol) and sodium cyanoborohydride (14 mg, 0.2 mmol). After stirring at room temperature for 2 hr, the reaction mixture was concentrated and passed through a reversed-phase column (0%-50% H2 MeCN in O) to give 5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide (17 mg, product Rate: 32%). MS: m / z 217.0 (M + H+ ).step 3 : N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -5-methyl-4,5,6, 7-tetrahydropyrazolo [1,5-a] pyrazine-2-sulfonamide is usedManufacturing method A Synthesized to deliver the desired product as a white solid (9.6 mg, yield: 29%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.80 (s, 1H), 8.02 (s, 1H), 6.94 (s, 1H), 6.55 (s, 1H), 4.16 (t,J = 5.6 Hz, 2H), 3.62 (s, 2H), 2.89 (t,J = 5.8 Hz, 2H), 2.79 (t,J = 7.2 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.40 (s, 3H), 1.99-1.93 (m, 4H). MS: m / z 416.1 (M + H+ ).Examples 67 The following shows 4,4-difluoro-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -4, Synthesis of 5,6,7-tetrahydropyrazolo [1,5-a] pyridine-3-sulfonamide. step 1 To a solution of 3-bromo-6,7-dihydropyrazolo [1,5-a] pyridine-4 (5H) -one (500 mg, 2.34 mmol) in DCM (5 mL) was added I2 (58 mg, 0.23 mmol) and propane-1,3-dithiol (276 mg, 2.57 mmol), and then the mixture was stirred at room temperature overnight. The reaction was then partitioned between DCM (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL),2 SO4 Dry and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 2/1) to give 3'-bromo-6 ', 7'-dihydro-5'H-spiro [[1,3] dithia Alkan-2,4'-pyrazolo [1,5-a] pyridine] (530 mg, yield: 75%).step 2 To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (1.61 g, 5.6 mmol) in DCM (5 mL) at -70 ° C was added HF. Pyridine (55%, 3.4 mL, 18.6 mmol) and 3'-bromo-6 ', 7'-dihydro-5'H-spiro [[1,3] dithiane-2,4'-pyrazolo [ 1,5-a] pyridine] (430 mg, 1.4 mmol). After stirring at room temperature for 1 hour, the reaction was partitioned between DCM (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (20 mL). The organic layers were combined, washed with brine (20 mL),2 SO4 Dry, filter and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 5/1) to give 3-bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridine (260 mg, yield: 57%). MS: m / z 236.9 (M + H+ ).step 3 N at -78 ° C2 Downward of 3-bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine (0.26 g, 1.1 mmol) in anhydrous THF (5 mL) To the solution was slowly added n-BuLi (0.44 mL, 1.1 mmol, 2.5 M) in hexane. After stirring at this temperature for 20 min, slowly add ZnCl in ether at this temperature.2 (1.1 mL, 1.1 mmol, 1 M). The cold bath was removed and the reaction was stirred at r.t. for 1 hr. To the mixture was added TCPC (0.33 g, 1.1 mmol) at 0 ° C and the mixture was stirred at r.t. for 1 hr. Saturate the reaction with saturated NH4 The Cl solution (2 mL) was quenched and partitioned between water (20 mL) and EA (20 mL). The organic layer was washed with brine (80 mL),2 SO4 Dry and concentrate to give crude 4,4-difluoro-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-3-sulfonic acid 2,4,6-triol as a yellow oil Chlorophenyl ester. The crude was dissolved in THF (5 mL) and NH was added to the solution3. H2 O (5 mL). After stirring at 60 ° C overnight, the reaction was concentrated to remove the solvent. The residue was acidified with 1 N HCl to pH = 5 and partitioned between EA (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with EA (20 mL). The organic layers were combined, washed with brine (30 mL),2 SO4 Dry, filter and concentrate in vacuo. The residue was purified by a silica gel column (PE / EA = 2/1) to give 4,4-difluoro-4,5,6,7-tetrahydropyrazolo [1,5-a] as a yellow solid Pyridine-3-sulfonamide (50 mg, yield: 19% over 2 steps). MS: m / z 238 (M + H+ ).step 4 4,4-difluoro-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -4,5, 6,7-tetrahydropyrazolo [1,5-a] pyridine-3-sulfonamideManufacturing method A Synthesized to deliver the desired product as a white solid (26 mg, yield: 28%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.65 (brs, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 4.28 (t,J = 5.6 Hz, 2H), 2.78 (t,J = 6.8 Hz, 4H), 2.60 (t,J = 6.8 Hz, 4H), 2.50 (overlapping, 2H), 2.20-2.11 (m, 2H), 1.99-1.91 (m, 4H). MS: m / z 437.0 (M + H+ ).Examples 68 The following shows N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-di Synthesis of hydrogen-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide.N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro- 5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is usedManufacturing method A Synthesized to deliver the desired product (210 mg, yield: 61%) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.51 (brs, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 4.45 (t,J = 5.2 Hz, 2H), 4.11 (t,J = 6.4 Hz, 2H), 2.82 (t,J = 7.6 Hz, 4H), 2.64 (t,J = 6.8 Hz, 4H), 2.22-2.17 (m, 2H), 2.05-1.98 (m, 4H). MS: m / z 421.1 (M + H+ ).Examples 69 The following shows N-((8-methyl-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7- Synthesis of Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide. step 1 A solution of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (1 g, 5.78 mmol) in DCM (20 mL) at 0 ° C. To this was added NBS (1.03 g, 5.78 mmol) and the mixture was stirred at 0 ° C for 2 hr. Pour the reaction mixture into H2 O (30 mL) and extracted with EA (50 mL x 2). The combined EA was washed with brine (100 mL),2 SO4 Dry and concentrate to dryness. Purification of the residue by a silica gel column (PE / EA = 50/1) yielded 8-bromo-1,2,3,5,6,7-hexahydro-s-dicyclopentadiene as a red solid. Phenyl-4-amine (838 mg, yield: 57%).1 H NMR (300 MHz, CDCl3 ): δ = 3.48 (brs, 2H), 2.91 (t,J = 7.5 Hz, 4H), 2.81 (t,J = 6.9 Hz, 4H), 2.19-2.06 (m, 4H).step 2 To 8-bromo-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-amine (200 mg, 0.79 mmol) in dioxane (8 mL) and H2 O (2 mL) was added to the solutionAcid (52 mg, 0.87 mmol), K2 CO3 (327 mg, 2.37 mmol) and Pd (PPh3 )4 (45 mg, 0.039 mmol) and2 Stir overnight. The reaction mixture was filtered through silica, and then by prep-HPLC (NH3 · H2 O) It was purified to give 8-methyl-1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-amine (26 mg, product Rate: 18%).step 3 N-((8-methyl-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,7-dihydro -5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is such asManufacturing method E Synthesized in to deliver the desired product as a white solid (14 mg, yield: 24%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.41 (s, 1H), 7.81 (s, 1H), 7.60 (s, 1H), 4.44 (t,J = 4.8 Hz, 2H), 4.11 (t,J = 5.6 Hz, 2H), 2.74 (t,J = 6.8 Hz, 4H), 2.69-2.58 (m, 4H), 2.21-2.17 (m, 2H), 2.08 (s, 3H), 2.00-1.92 (m, 4H). MS: m / z 417.0 (M + H+ ).Examples 70 Shown below (R )-((4-chloro-2,6-diisopropylphenyl) aminomethyl) ((6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b Synthesis of [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium. step 1 To a solution of 2,6-diisopropyl-phenylamine (2.4 g, 13.5 mmol) in DMF (20 mL) was added NCS (1.9 g, 14.2 mmol) in one portion. After stirring for 16 hr at room temperature, the reaction mixture was poured into water (100 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2),2 SO4 Dry and concentrate. The residue was purified by a silica gel column (PE / EA = 50/1) to give 4-chloro-2,6-diisopropyl-phenylamine (2.0 g, yield: 70%) as a red oil.step 2 (R )-((4-chloro-2,6-diisopropylphenyl) aminomethyl) ((6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) phosphoniumManufacturing method E Synthesized in to deliver the desired product as a white solid (50 mg, yield: 51%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.38 (s, 1H), 7.33 (s, 1H), 7.00 (s, 2H), 4.49-4.45 (m, 1H), 4.18-4.08 (m, 3H), 4.00-3.90 (m, 1H ), 3.34 (s, 3H), 3.20-3.05 (m, 2H), 1.05-1.03 (m, 12H). MS: m / z 471.0 (M + H+ ).Examples 71 The following shows N-((8-chloro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -6,6-di Synthesis of methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide.N, N-Dimethylpyridin-4-amine (0.657 mmol, 0.080 g) was dissolved in THF (1.5 mL) and then di-t-butyl dicarbonate (0.626 mmol, 0.144 mL) was slowly added to THF ( 1.5 mL). After stirring for several minutes, 8-chloro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzo-4-amine (0.626 mmol, 130 mg) was added in THF (1 mL) The solution was stirred and the mixture was stirred for 30 min. At the same time, 6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide in THF (1 mL) ( 0.626 mmol, 0.145 g) was treated with sodium hydride (0.626 mmol, 0.023 g) and stirred for 30 min. At this point, the two solutions were mixed and stirred for 18 h. The reaction was then saturated with NH4 Cl (10 mL) was quenched and diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were then washed with water (10 mL) and concentrated. The resulting solid was suspended in MeOH (5 mL), filtered, and filtered by prep HPLC (10-40% MeCN: 10 mM aq.NH4 OH). The purified fractions were combined and concentrated to give N-((8-chloro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) as a white solid Carbamoyl) -6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (4 mg, 1.374%).1 H-NMR (400 MHz; MeOD): δ 7.68 (s, 1H), 4.08 (s, 2H), 3.86 (s, 3H), 2.90-2.87 (m, 4H), 2.80-2.76 (m, 4H), 2.09-2.02 (m, 5H), 1.11 (s, 6H). MS: m / z 465.0 (M + H+ ).Examples 72 The following shows N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) aminomethane) -6,7-dihydro-5H-pyrazolo [5,1 -b] Synthesis of [1,3] oxazine-3-sulfonamide.Dissolve 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (100 mg, 0.492 mmol) in MeOH (4 mL )in. Then sodium methoxide (0.106 g, 0.492 mmol) was added and the mixture was stirred for 30 min. The solvent was then evaporated and 7-isocyanato-2,2-dimethyl-2,3-dihydrobenzofuran (0.093 g, 0.492 mmol) in MeCN (4 mL) was added and the mixture was stirred overnight. At this time, the reaction was filtered and the filter residue was washed with EtOAc and dried to give N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) amine formamidine as a cream solid) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (108.5 mg, 56.19%). MS: m / z 393 (M + H+ ).Examples 73 The following shows N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) -2-methyl-6,7- Synthesis of Dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide.2-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide is based on 6,7-dihydro-5H-pyridine Zolo [5,1-b] [1,3] oxazine-3-sulfonamide is prepared in the same manner, except that the appropriate 3-methyl-3-pyrazolin-5-one is used as the starting material. Add 2-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (80 mg, 0.368 mmol), 4-isocyanate Acid-1,2,3,5,6,7-hexahydro-s dicyclopentadiene benzo (0.073 g, 0.368 mmol) and sodium hydride (13.595 mg, 0.368 mmol) in DMF (5 mL) Mix and stir overnight. The reaction was then quenched with water and the white solid was filtered. The filtrate was concentrated and the residue was suspended in acetone (10 mL), filtered and washed with acetone, and then dried to give N-(((1,2,3,5,6,7-hexahydro-s- Dicyclopentadienyl-4-yl) carbamyl) -2-methyl-6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine- 3-Sulfonamide (51.4 mg, 33.51%). MS: m / z 417 (M + H+ ).Examples 74 The following shows N-((4-cyano-2,6-diisopropylphenyl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1, 3] Synthesis of oxazine-3-sulfonamide.Add Et to a solution of 4-amino-3,5-diisopropylbenzonitrile (300 mg, 1.48 mmol) in anhydrous THF (10 mL) at r.t.3 N (0.41 mL, 2.97 mmol) followed by triphosgene (220 mg, 0.74 mmol). The reaction mixture was heated at 60 ° C for 1 hr, then cooled to r.t. and partitioned between EtOAc (30 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), and dried over Na2 SO4 Dry and concentrate under reduced pressure to give a yellow solid (210 mg, 62%). The solid (100 mg, 0.44 mmol) was dissolved in anhydrous DMF (1 mL). To this solution was added 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (90 mg, 0.44 mmol) at rt and then NaH (60% in mineral oil, 17 mg, 0.44 mmol). The reaction was stirred for 1 hr before MeOH (3 mL) was added. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography (MeOH / DCM 0 to 5%) to obtain N-((4-cyano-2,6-diisopropylbenzene) as a white solid. Yl) carbamoyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (36.3 mg, 19%). MS: m / z 432 (M + H+ ).Examples 75 The following shows N-((4-chloro-2,6-dicyclopropylphenyl) aminomethylamidino) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3 Synthesis of oxazine-3-sulfonamide.Add Et to a solution of 4-chloro-2,6-dicyclopropylaniline (180 mg, 0.87 mmol) in anhydrous THF (10 mL) at r.t.3 N (0.24 mL, 1.73 mmol), followed by triphosgene (130 mg, 0.43 mmol). The reaction mixture was heated at 60 ° C for 1 hr, then cooled to r.t., and partitioned between EtOAc (30 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), and dried over Na2 SO4 Dry and concentrate under reduced pressure to give a pale yellow solid (170 mg, 84%). The solid (100 mg, 0.49 mmol) was dissolved in anhydrous DMF (1 mL). To this solution was added 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (115 mg, 0.49 mmol) at rt and then NaH (60% in mineral oil, 20 mg, 0.49 mmol). The reaction mixture was stirred at RT for 1 hr before MeOH (3 mL) was added. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography (MeOH / DCM 0 to 5%) to obtain N-((4-chloro-2,6-dicyclopropylphenyl) as a white solid ) Carboxamidine) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (37.7 mg, 17%). MS: m / z 437 (M + H+ ).Examples 76 N-((3,5-Dicyclopropylphenyl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3- Synthesis of SulfonamideAdd Et to a solution of 3,5-dicyclopropylaniline (200 mg, 1.15 mmol) in anhydrous THF (10 mL) at r.t.3 N (0.27 mL, 2.0 mmol) followed by triphosgene (120 mg, 0.39 mmol). The reaction was stirred for 2 hr before the THF was removed. The resulting residue was suspended in hexane (50 mL), the insoluble white solid was removed by vacuum filtration and the hexane was removed under reduced pressure, resulting in a clear oil. The obtained oil was then dissolved in anhydrous DMF (2 mL). To this solution was added 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (80 mg, 0.39 mmol) at rt and then NaH (60% in mineral oil, 20 mg, 0.49 mmol). The reaction mixture was stirred for 1 hr before MeOH (5 mL) was added. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography (MeOH / DCM 0 to 10%) to obtain N-((3,5-dicyclopropylphenyl) amine formamidine as a white solid ) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (90 mg, 57%). MS: m / z 403 (M + H+ ).Examples 77 The following shows N-((7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl) aminomethane) -6,7-dihydro-5H-pyrazolo [ Synthesis of 5,1-b] [1,3] oxazine-3-sulfonamide.Et was added to a solution of 7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-amine (85 mg, 0.41 mmol) in anhydrous THF (10 mL) at r.t.3 N (0.17 mL, 1.2 mmol) followed by triphosgene (60 mg, 0.20 mmol). The reaction mixture was heated at 60 ° C for 1 hr, then cooled to r.t. and partitioned between EtOAc (30 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), and dried over Na2 SO4 Dry and concentrate under reduced pressure to give a yellow oil. The obtained oil was then dissolved in anhydrous DMF (1 mL). To this solution was added 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (50 mg, 0.25 mmol) at rt and then NaH (60% in mineral oil, 16 mg, 0.41 mmol). The reaction mixture was stirred for 1 hr before MeOH (5 mL) was added. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography (MeOH / DCM 0 to 10%) to obtain N-(((7-chloro-5-cyclopropyl-2,3) as a pale yellow solid -Dihydro-1H-inden-4-yl) aminomethylfluorenyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (60 mg, 57%). MS: m / z 437 (M + H+ ).Examples 78 The following shows N-((1,2,3,4-tetrahydroacridin-9-yl) aminomethyl) -6,7-dihydro-5H-pyrazolo [5,1-b] [1 , 3] Synthesis of oxazine-3-sulfonamide.Add Et to a solution of 1,2,3,4-tetrahydroacridin-9-amine (200 mg, 1.01 mmol) in anhydrous THF (10 mL) at r.t.3 N (0.17 mL, 1.2 mmol) followed by triphosgene (150 mg, 0.49 mmol). The reaction mixture was heated at 60 ° C for 2 hr, and then cooled to RT. The THF was removed and the resulting residue was suspended in hexane (50 mL), the insoluble white solid was removed by vacuum filtration and the hexane was removed under reduced pressure, resulting in a yellow oil. The obtained oil was then dissolved in anhydrous DMF (1 mL). To this solution was added 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (50 mg, 0.25 mmol) at rt and then NaH (60% in mineral oil, 20 mg, 0.49 mmol). The reaction mixture was stirred for 1 hr before MeOH (1 mL) was added. The residue was purified by pre-HPLC (MeCN / water / 0.1% formic acid) to obtain N-((1,2,3,4-tetrahydroacridin-9-yl) aminomethyl)-as a white solid 6,7-dihydro-5H-pyrazolo [5,1-b] [1,3] oxazine-3-sulfonamide (1.8 mg, 2%). MS: m / z 428 (M + H+ ).Examples 79 The following shows ((6- (aminomethyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amine Fluorenyl) sulfonamide sodium and ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl)) ((6-((2 , 2,2-trifluoroacetamido) methyl) -6,7-dihydro-5H -Pyrazolo [5,1-b Synthesis of [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium. step 1 : Will (6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-yl) methylamine (crude, about 1.2 mmol) was dissolved in TFAA (3 mL). After heating the solution under reflux for 3 hr, it was quenched with the addition of EA (20 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with EA (10 mL x 3). The organic layers were combined and washed with brine (10 mL) and dried over anhydrous Na2 SO4 dry. The solution was concentrated in vacuo. Purification of the residue by a silica gel column (PE / EA = 1/1) gave a yellow solidN -((6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-yl) methyl) -2,2,2-trifluoroacetamide (140 mg, yield: 47%). MS: m / z 250.2 (M + H+ ).step 2 : At 0 ℃N -((6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-yl) methyl) -2,2,2-trifluoroacetamidamine (140 mg, 0.56 mmol) in DCM (3 mL) was added dropwise ClSO3 H (0.11 mL, 1.68 mmol). After stirring at room temperature for 16 hr, pyridine (0.14 mL, 1.68 mmol) was added dropwise at 0 ° C. And then add PCl in portions at 0 ° C5 (350 mg, 1.68 mmol). The reaction mixture was stirred at room temperature for 1 hr, poured into ice water (2 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2 SO4 Dry and concentrate to give the crude product, which was used directly in the next step without further purification.step 3 : To 6-((2,2,2-trifluoroacetamido) methyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazine-3-sulfosulfonyl chloride (crude, about 0.56 mmol) in THF (3 mL) was added with NH3 .H2 O (3 mL). After stirring at 60 ° C for 2 hr, the reaction mixture was concentrated to about 1 mL. The residual suspension was acidified to pH = 3 with 1 M aq. HCl and filtered. With reversed phase columns (MeCN / H2 O) The filtrate was purified to give 2,2,2-trifluoro- as a yellow solidN -((3-Aminosulfonyl-6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-yl) methyl) acetamide (120 mg, yield: 65%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.58 (s, 1H), 4.51 (dd,J = 11.2, 2.8 Hz, 1H), 4.32-4.23 (m, 2H), 3.96 (dd,J = 12.4, 3.2 Hz, 1H), 3.44 (d,J = 7.2 Hz, 2H), 2.73-2.64 (m, 1H).step 4 : toN -((3-Aminosulfonyl-6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-yl) methyl) acetamide (60 mg, 0.18 mmol) in a suspension of DMSO (2 mL) was added MeONa (10.7 mg, 0.2 mmol) and the mixture was dissolved in Stir for 20 min at room temperature to produce a sodium salt suspension. In another flask, add 1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-ylamine (38 mg, 0.22 mmol) and TEA (54 mg, 0 54 mmol) in THF (2 mL) was added triphosgene (24 mg, 0.80 mmol) in one portion and the mixture was stirred at room temperature under N2 Stir for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 16 hr. After that, the suspension was filtered, and passed through a reversed-phase column (MeCN / H2 O) The filtrate was purified to give ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6- ((2,2,2-trifluoroacetamido) methyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium (44 mg, yield: 44%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 9.69 (t,J = 5.6 Hz, 1H), 7.53 (brs, 1H), 7.41 (s, 1H), 6.80 (s, 1H), 4.37 (dd,J = 10.8, 2.8 Hz, 1H), 4.19-4.11 (m, 2H), 3.88 (dd,J = 12.0, 7.6 Hz, 1H), 3.30-3.25 (m, 2H), 2.75 (t,J = 7.2 Hz, 4H), 2.66-2.59 (m, 5H), 1.95-1.85 (m, 4H). MS: m / z 528.1 (M + H+ ).step 5: To ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) aminomethyl) ((6-((2,2,2-tri Fluoroacetamido) methyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfonyl) sulfonamide sodium (7 mg, 0.01 mmol) in DMSO (1 mL) was added with an aqueous solution of NaOH (0.5 mL, 1 mmol, 2 M) The mixture was stirred at room temperature for 48 hr. Thereafter, the suspension was filtered and passed through a reversed-phase column (MeCN / H2 O) The filtrate was purified to give ((6- (aminomethyl) -6,7-dihydro-5) as a white solidH -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) ((1,2,3,5,6,7-hexahydro-s-dicyclopentadienyl-4-yl) amine Fluorenyl) ammonium sodium (4.9 mg, yield: 84%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.45 (brs, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 4.37 (dd,J = 10.8, 3.2 Hz, 1H), 4.13-4.02 (m, 2H), 3.82 (dd,J = 12.4, 8.0 Hz, 1H), 2.74 (t,J = 6.8 Hz, 4H), 2.68-2.57 (m, 6H), 2.30-2.12 (m, 1H), 1.94-1.85 (m, 4H). MS: m / z 432.1 (M + H+ ).Examples 80 Shown below (R )-((4-fluoro-2,6-diisopropylphenyl) aminomethyl) ((6-methoxy-6,7-dihydro-5H -Pyrazolo [5,1-b Synthesis of [1,3] oxazin-3-yl) sulfofluorenyl) fluorenamide. step 1 In N2 Neutral 2,6-dibromo-4-fluoroaniline (2.0 g, 7.4 mmol), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3 , 2-dioxaborane (3.37 g, 20.1 mmol), Cs2 CO3 (7.23 g, 22.2 mmol) and H2 O (4 mL) in dioxane (40 mL) was added with Pd (dppf) Cl2 (0.54 g, 0.74 mmol). The reaction mixture was stirred at 100 ° C overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 10/1) to give 4-fluoro-2,6-bis (prop-1-en-2-yl) aniline (1.10 g, 78%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 6.72 (d,J = 9.6 Hz, 2H), 5.29 (t,J = 1.6 Hz, 2H), 5.01 (d,J = 1.2 Hz, 2H), 4.24 (s, 2H), 2.01 (s, 6H).step 2 To a solution of 4-fluoro-2,6-bis (prop-1-en-2-yl) aniline (1.10 g, 5.7 mmol) in MeOH (30 mL) was added Pd / C (0.11 g, 10% wt ). Degas the reaction mixture and use H2 Purge three times. Place it at room temperature in H2 Stir under balloon atmosphere overnight and monitor by LCMS. The mixture was filtered. The filtrate was concentrated in vacuo to give 4-fluoro-2,6-diisopropylaniline (1.05 g, 94%) as a brown oil.1 H NMR (400 MHz, DMSO-d 6 ): δ = 6.67 (d,J = 10.0 Hz, 2H), 4.44 (brs, 2H), 3.07-3.01 (m, 2H), 1.16-1.10 (m, 12H).step 3 At -5 ℃ to (R ) -6-methoxy-6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] Xazine-3-sulfamethoxamine (55 mg, 0.25 mmol) in THF (5 mL) was added with MeONa (15 mg, 0.28 mmol). The reaction mixture was then stirred at -5 ° C for 30 min. Separately, to a solution of 4-fluoro-2,6-diisopropylaniline (45 mg, 0.23 mmol) in THF (5 mL) at -5 ° C was added triphosgene (27 mg, 0.092 mmol) and TEA (47 mg, 0.46 mmol). The reaction mixture was then stirred at -5 ° C for 30 min. The reaction was filtered and the filtrate was added to the solution from the first step at -5 ° C.R )-((6-methoxy-6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium suspension. The reaction was stirred at room temperature overnight. After removing the solvent in vacuo, the residue was purified by prep-HPLC to give a white solid (R )-((4-fluoro-2,6-diisopropylphenyl) aminomethyl) ((6-methoxy-6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium (28.2 mg, 27%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.65 (s, 1H), 7.57 (s, 1H), 6.91 (d,J = 9.6 Hz, 2H), 4.63 (d,J = 11.6 Hz, 1H), 4.31 (d,J = 11.6 Hz, 1H), 4.22 (d,J = 1.6 Hz, 2H), 4.06 (s, 1H), 3.36 (s, 3H), 2.96-2.86 (m, 2H), 1.05 (s, 12H). MS: m / z 455.1 (M + H+ ).Examples 81 (R )-((4-fluoro-2,6-diisopropylphenyl) aminomethyl) ((6- (methylamino) -6,7-dihydro-5H -Pyrazolo [5,1-b Synthesis of] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium step 1 At -5 ℃ to (R ) -Methyl (3-Aminosulfonyl-6,7-dihydro-5H -Pyrazolo [5,1-b To a solution of [[1,3] oxazin-6-yl) aminocarboxylic acid third butyl ester (375 mg, 1.13 mmol) in THF (10 mL) was added MeONa (165 mg, 3.06 mmol). The reaction mixture was then stirred at -5 ° C for 30 min. Separately, to a solution of 4-fluoro-2,6-diisopropylaniline (200 mg, 1.02 mmol) in THF (5 mL) at -5 ° C was added triphosgene (121 mg, 0.41 mmol) and TEA (0.28 mL, 2.04 mmol). The reaction mixture was then stirred at -5 ° C for 30 min and monitored by TLC. The reaction was filtered and the filtrate was added to the solution from the first step at -5 ° C.R )-((6-((third-butoxycarbonyl) (methyl) amino) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium suspension. The reaction was stirred at room temperature overnight. After removing the solvent in vacuo, the residue was purified by flash column chromatography to give a yellow solid (R )-(3- (N -((4-fluoro-2,6-diisopropylphenyl) aminomethylamido) sulfamoyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-yl) (methyl) carbamic acid third butyl ester (237 mg, 43%).step 2 to(R )-(3- (N -((4-fluoro-2,6-diisopropylphenyl) aminomethylamido) sulfamoyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-6-yl) (methyl) aminocarboxylic acid third butyl ester (100 mg, 0.18 mmol) in DCM (2 mL) was added with CF3 CO2 H (5 mL). The reaction mixture was then stirred at room temperature for 20 min. The mixture was basified with 4 M aq. NaOH to pH = 12 at -5 ° C. The aqueous layer was concentrated in vacuo. The residue was purified by flash column chromatography to give a yellow solid (R )-((4-fluoro-2,6-diisopropylphenyl) aminomethyl) ((6- (methylamino) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium (23.6 mg, 23%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.67 (s, 1H), 7.57 (s, 1H), 6.92 (d,J = 10.0 Hz, 2H), 4.40-4.28 (m, 2H), 4.22 (dd,J = 12.4, 4.4 Hz, 1H), 3.94 (dd,J = 12.8, 4.4 Hz, 1H), 3.21-3.16 (m, 1H), 2.95-2.85 (m, 2H), 2.34 (s, 3H) 1.09-1.00 (m, 12H). MS: m / z 454.2 (M + H+ ).Examples 82 Shown belowN -((4-fluoro-2,6-diisopropylphenyl) aminomethyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] Synthesis of oxazine-3-sulfonamide. step 1 At 6,7-dihydro-5 at -5 ° CH -Pyrazolo [5,1-b ] [1,3] Xazine-3-sulfamethoxamine (100 mg, 0.45 mmol) in THF (5 mL) was added with MeONa (73 mg, 1.35 mmol) and DMSO (1 mL). The reaction mixture was then stirred at -5 ° C for 30 min. Separately, to a solution of 4-fluoro-2,6-diisopropylaniline (100 mg, 0.45 mmol) in THF (5 mL) at -5 ° C was added triphosgene (53 mg, 0.18 mmol) and TEA (0.13 mL, 0.90 mmol). The reaction mixture was then stirred at -5 ° C for 30 min. The reaction was filtered and the filtrate was added to the ((6,7-dihydro-5) from the first step at -5 ° C.H -Pyrazolo [5,1-b ] [1,3] oxazin-3-yl) sulfofluorenyl) sulfonamide sodium suspension. The reaction was stirred at room temperature overnight. After removing the solvent in vacuo, the residue was purified by prep-HPLC to give a white solidN -((4-fluoro-2,6-diisopropylphenyl) aminomethyl) -6,7-dihydro-5H -Pyrazolo [5,1-b ] [1,3] oxazine-3-sulfonamide (103.5 mg, 54%).1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.52 (brs, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 6.89 (d,J = 10.0 Hz, 2H), 4.39 (t,J = 4.8 Hz, 2H), 4.08 (t,J = 6.4 Hz, 2H), 3.00-2.90 (m, 2H), 2.24-2.14 (m, 2H), 1.04 (s, 12H). MS: m / z 424.8 (M + H+ ).Biological test method abbreviation PBMC: peripheral blood mononuclear cells KC: Kupffer cells FBS: fetal bovine serum LPS: lipopolysaccharide NLRP3 Activation and inhibition analysis Some of the following analyses were used to determine the inhibitory activity of a compound on NLRP3 inflammasome using the common inflammator activation stimulator nigericin.Biological examples 1 : Cell culture Human peripheral blood mononuclear cells (PBMCs) consisting of lymphocytes (T, B and NK cells), monocytes and dendritic cells were freshly isolated from human peripheral blood from healthy donors. Cells were obtained via a donor program approved by the IRB of iXCells Biotechnologies, all of which were tested for bacterial and viral infections. Cells were purified from peripheral blood using polysucrose gradient centrifugation. Human Kupffer cells (KC), specialized liver macrophages residing in the space of Disse, were obtained by gradient separation of freely harvested liver samples from Samsara Sciences after death. Cells were obtained via a donor program approved by the IRB of Samsara Sciences, and all donors were tested negative for bacterial and viral infections.Biological examples 2 : NLRP3 Inflammatory body activation analysis Store fresh or frozen PMBC at 0.5-1 × 10 per well5 Cells were seeded in a V-bottom 96-well plate and incubated at 37 ° C, 5% CO2 RPMI 1640 medium with GlutaMAX supplement, 4.5 g / L D-glucose, 10% fetal bovine serum (FBS), 100 mM sodium pyruvate, 1% penicillin / streptomycin, 10 mM HEPES, and 0.05 mM β-mercaptoethanol Incubate overnight. Freshly isolated or cryopreserved KC cells at 0.6-1.5 × 105 Cells / well were seeded in flat-bottomed 96-well plates at 37 ° C, 5% CO2 The cells were incubated overnight in RPMI 1640 medium with GlutaMAX supplement, FBS, 1% penicillin / streptomycin, and 10 mM HEPES. The next day, cells were primed with 100 ng / mL lipopolysaccharide (LPS; Sigma Aldrich) in FBS-free RPMI 1640 for 3 hours. After the prime step, remove the culture medium and pre-incubate PBMC in FBS-free medium with continuous concentrations of test compound (0.00017-10 uM) or vehicle (DMSO) for 30 minutes before adding NLRP3 activator. Cells were then stimulated with 10 uM Nigerianin (Sigma Aldrich; InvivoGen) for 1.5 h. The plate was centrifuged at 1,500 rpm for 3 minutes to pellet the cells, and the supernatant was transferred to a new plate for subsequent experiments. Measurement of cytokines / NLRP3 Evaluation of Inflammatory Activity For ELISA analysis, cells were seeded into 96-well plates. After the study, the supernatant was removed and the contents of mature IL-1β, IL18 and TNFα (Quantikine ELISA, R & D systems) were measured in cell conditioned medium by ELISA according to the manufacturer's instructions. result The results of certain compounds are shown below. Biological examples 3 : CTG (CellTitre-Glo) analysis CellTiter-Glo® analysis (Promega, Madison, WI) was used to measure the survival rate of compound-treated cells. This analysis measures the ATP content of cells proportional to the number of live cells in the well. This is used to establish a counter-screening that is not due to cytotoxicity, but through inhibition of the inflammasome pathway, in the reduction of IL-1β content in cells treated with LPS and Nigerian bacteriocin and treated with compounds. Compounds that inhibit the activation of NRLP3 inflammasomes ultimately increase the survival rate of LPS and nigerin-stimulated cells by blocking NLRP3-mediated cell scoring (which would otherwise cause lysis).Biological examples 4 : TNF-α The TNFα content of cells stimulated by LPS and nicotin was measured by HTRF analysis (Cisbio, Bedford, MA). Inflammatory pathway-selective compounds do not inhibit TNF [alpha] production that relies solely on LPS stimulation through the TLR4 / NFkB pathway pathway. Measuring TNFα production is also used as a technical counter-screening to eliminate compounds that interfere with HTRF reagents. Therefore, compounds that inhibit the contents of IL-1β and TNFα were classified as non-selective to inflamed bodies or interfered with HTRF readout. Additional analysis Use some of the following analyses.Biological examples 5 : Human Microsomal Stability (Eh) DMSO was used as a diluent to prepare a stock solution of the test substance and the positive control at a concentration of 10 mM. All stock solutions were then diluted with 70% acetonitrile to a working concentration of 0.25 mM. The cofactor used in this study was the NADPH regeneration system, which consisted of 6.5 mM NADP, 16.5 mM G-6-P, and 3 U / mL G-6-P D. The quenching reagent consists of acetonitrile containing tolbutamide and propanolol (used as an internal standard). The incubation mixture contained 0.5 mg / mL liver microsomal protein and 1 μM test substance / positive control in 100 mM potassium phosphate buffer. A 0-minute sample was prepared by adding an 80 µL aliquot of each incubation mixture to 300 µL of quenching reagent to precipitate the protein. Vortex the sample and then add a 20 µL aliquot of the NADPH regeneration system. The reaction was initiated by adding 80 µL of the NADPH regeneration system to 320 µL of each incubation mixture. The final incubation conditions reached in 400 µL: 0.5 mg / mL microsomal protein, 1 µM test substance / positive control, 1.3 mM NADP, 3.3 mM glucose 6 phosphate, 0.6 U / mL glucose 6 phosphate dehydrogenase. The mixture was incubated in a 37 ° C water bath with gentle shaking. At 10 minutes, 30 minutes, 90 minutes, remove 100 µL aliquots of each mixture to a clean 96-well plate (containing 300 µL of quenching reagent to precipitate proteins) and centrifuge (4000 × g, 10 min). 80 μL of the supernatant was placed in a 96-well analysis plate pre-added with 160 μL of ultrapure water, and then analyzed by LC-MS / MS. Assuming human liver blood flow is 20.7 mL / min / kg, the liver extraction rate (Eh) value is calculated from the measured in vitro clearance. An Eh value of <0.3 indicates that the compound has favorable metabolic stability.Biological examples 6 : Lipophilic: The LogD plug-in from ChemAxon was used to calculate the lipophilicity (as represented by logD) of certain compounds, as shown in the table below. Several publications in recent years have linked the clinical success of drug candidates to their physical properties. For example, the degree of lipophilicity can be a factor in the success of a drug candidate. In "Lipophilicity in Drug Discovery" (Waring, Expert Opinion on Drug Discovery, Vol. 5, 2010-No. 3, pp. 235-248, which is incorporated herein by reference), the author's analysis of attrition indicates that The optimal lipophilicity of the molecular drug (as measured by logD) is somewhere between 1 and 3. The design of compounds outside this range can introduce undesirable tendencies (ie, ADMET, promiscuity). Care should be taken when adding non-polar atoms during drug discovery lead optimization to identify quality molecules that can successfully pass clinical trials. By way of example, the pyrazolo-oxazines described herein may provide a favorable position regarding lipophilicity. As an example, a cyclic saturated ring avoids an increase in clogD of about 0.7 log units when compared to an analog with a similar number of non-polar atoms.In addition, the oxazine ring is provided with a scaffold with polar atoms, producing a clogD of 1.8. This may allow further processing with other substituents, such as non-polar substituents, without exceeding the ideal range described herein.result Results for certain compounds are shown below and in Figures 1 and 2. The PBMC IL-1β IC50 and KC IL-1β IC50 are explained above. A ＜ 100nM, B 100nM-1µM, C 1-10µM, D ＞ 10µM Biological examples 7 : C57BL / 6 Injection in mice LPS / ATP Effect of post-treatment on interleukin production summary : The effects of compound 1 and 2 treatment on the NLRP3-dependent release of IL-1β and TNFα interleukin were explored in an acute in vivo LPS / ATP challenge model. After a single oral dose of 1.5 mg / kg and 5 mg / kg of compound 1 and 1 mg / kg and 2.5 mg / kg of compound 2, at a time point of 3.5 hours, relative to vehicle-treated animals, from LPS The level of IL-1β in peritoneal lavage fluid of mice challenged with ATP decreased by> 98%. After a single oral dose, at a time point of 3.5 hours, relative to vehicle-treated animals, the release of IL-1β was reduced by> 79% at 0.5 mg / kg of Compound 1, and at 0.25 mg / kg of Compound 2 > 57%. There was no significant change in TNFα content in any group compared to vehicle-treated animals. Compound 1:Compound 2:Compound 3:Compound 4:Compound 5: Research objectives : The purpose of this study was to determine the effects of Compounds 1 and 2 treatment on the production of interleukins after injection of LPS / ATP in female C57BL / 6 mice.Experiment design and procedure: The key study parameters are shown in Table 1. Mice were acclimated to the facility for at least 7 days before the study began. On day -1, mice were weighed and assigned to groups in a balanced manner according to Table 2 (see below) to achieve similar average body weights between groups at the beginning of the study. * Calibrated for salt content. At -1 hour, all mice received a single dose of treatment or vehicle. At 0 hours, all mice received 1 μg of ultrapure lipopolysaccharide (LPS, lnvivoGen, San Diego, CA) intraperitoneally. At 2 hours (2 hours after LPS injection), all mice were injected intraperitoneally with 0.5 ml of 80 mM disodium ATP (Sigma, pH was adjusted to 7.2 before injection). At 2.5 hours (30 minutes after ATP injection and 3.5 hours after compound administration), blood from all mice was collected into K2 EDTA tubes via retro-orbital hemorrhage, and plasma was prepared and stored at 80 ° C. Choose to ship the sample to the customer or customer's supplier within 7 days of completing this study. Immediately after blood collection, each mouse was euthanized, and the peritoneal cavity was rinsed with 3 ml of ice-cold PBS containing 25 U / ml of heparin sodium salt, a protease inhibitor mixture (complete ™ ULTRA Tablets, Sigma, Roche) and 10% FBS. Collect approximately 1 ml of lavage fluid, spin to remove cells and store the supernatant at -80 ° C. The vehicle of compound 1 was PBS, and the vehicle of compound 2 was 0.5% methyl cellulose. The compound powder was stored at 4 ° C. All compounds were prepared fresh. The compound is weighed out and ground first with a mortar and pestle, followed by grinding with a small amount of vehicle. The mortar was then repeatedly washed with vehicle to remove all material and reach the correct concentration. The final solution was vortexed to produce a homogeneous mixture.Cytokines Analysis: According to the manufacturer's protocol, Becton Dickinson (Franklin Lakes, NJ) CBA analysis kits were used to determine mouse IL-1β and TNFα concentrations in peritoneal lavage fluid samples. A single analysis was performed for each sample.Statistical Analysis : The Student t-test was used to compare cytokinin concentrations.result : The effects of Compound 1 and Compound 2 treatment on IL-1β interleukin production were evaluated in the LPS / ATP injection model. Oral administration of 0.5 mg / kg, 1.5 mg / kg, and 5 mg / kg of Compound 1 or 0.25 mg / kg, 1 mg / kg, and 2.5 mg / kg of Compound 2 to female C57BL / 6 mice, using Becton The Dickinson CBA analysis kit measures the relative amount of IL-lβ (pg / ml). After a single oral dose of 1.5 mg / kg and 5 mg / kg of compound 1 and 1 mg / kg and 2.5 mg / kg of compound 2, at a time point of 3.5 hours, relative to vehicle-treated animals, from LPS IL-1β content in peritoneal lavage fluid of mice challenged with ATP was reduced by> 98% (Tables 3 and 4, Figure 3). After a single oral dose, at a time point of 3.5 hours, relative to vehicle-treated animals, the release of IL-1β was reduced by> 79% at 0.5 mg / kg of Compound 1, and at 0.25 mg / kg of Compound 2 > 57%. There was no significant change in TNFα content in any group compared to vehicle-treated animals (Tables 3 and 4, Figure 4). The effect of Compound 3 treatment on IL-1β interleukin production was evaluated in the LPS / ATP injection model. Female C57BL / 6 mice were orally administered Compound 3 at 0.25 mg / kg, 1 mg / kg, and 2.5 mg / kg, and the relative amount of IL-1β (pg / ml) was determined using a Becton Dickinson CBA analysis kit. After a single oral dose of Compound 2 at 1 mg / kg and 2.5 mg / kg, at a time point of 3.5 hours, in the peritoneal lavage fluid from mice treated with LPS plus ATP, at a time point of 3.5 hours, The IL-1β content was reduced by> 96% (Table 5, Figure 5). in conclusion : Explore the effects of Compound 1 and Compound 2 treatment on the NLRP3-dependent release of IL-lβ cytokines in an acute in vivo LPS / ATP challenge model. After a single oral dose of 1.5 mg / kg and 5 mg / kg of compound 1 and 1 mg / kg and 2.5 mg / kg of compound 2, at a time point of 3.5 hours, relative to vehicle-treated animals, from LPS The level of IL-1β in peritoneal lavage fluid of mice challenged with ATP decreased by> 98%. After a single oral dose, at a 3.5 hour time point, relative to vehicle-treated animals, IL-1β release was reduced by> 79% at 0.5 mg / kg Compound 1, and at 0.25 mg / kg Compound 2 > 57%. There was no significant change in TNFα content in any group compared to vehicle-treated animals.Biological examples 8 : Caspase 1 Inhibition of activation Materials and methods Cell culture Bone marrow cells were collected from freshly harvested mouse bones from 16 Black 6 mice, each from 4 bones (2 tibia and 2 femurs). Fresh delivery of bone in complete BMDM medium: RPMI 1640 medium, GlutaMAX ™ supplement, 1% non-essential amino acid, 1% penicillin / streptomycin, 10 mM HEPES, 0.05 mM β-ME, 20 ng / ml GM- CSF and 10% FBS. The top and bottom were cut off with scissors, and the cells were carefully washed from each bone with complete BMDM medium using a 25G needle. The cells were passed through a 100 μm cell filter and then centrifuged at 250 g. CD14 was isolated via magnetic negative selection using EasySep mouse mononuclear sphere separation kit (StemCell Technologies) according to the manufacturer's instructions+ cell. Approximately 2 ml of cells were run through 3 independent purification procedures. The total number of cells is approximately 12.7 million. CD14+ Cells were seeded into 96-well plates at 25,000 cells / well. The complete BMDM medium was changed every 3 days. The experiment was performed on the 9th day after the inoculation.Inflammatory body activation Bone marrow-derived macrophages (BMDM) were pre-incubated with the specified concentration of DMSO or compound for 30 minutes, and then stimulated with 100 ng / ml LPS. Place cells at 37 ° C, 5% CO2 Incubate for 3 hours in the environment. The cells were then further stimulated with 10 μM nigerin, and at 37 ° C, 5% CO2 Incubate for 90 minutes. Supernatants were collected at the end of the incubation period and analyzed for cytokines. Cells were harvested for Western blot analysis or tested for survival using CellTiter-Glo (Promega).Western blot method Cell samples from 96-well plates were prepared by lysing cells in situ with 50 μl of 4x NuPAGE LDS sample buffer (Fisher) + 5% β-mercaptoethanol. The plate was placed on a plate shaker at 700 rpm for 1 hour, and then ultrasonically treated for 10 minutes. The cell lysate was transferred to a PCR plate and heated to 95 ° C for 5 min. Samples were run on a NuPAGE Bis-Tris gel (Fisher) and transferred to a PVDF membrane using the iBlot 2 system (Fisher). Block the PVDF membrane in Azure Blot Wash Buffer (Azure Biosystems) + 5% low-fat milk powder for at least 5 min. Detection of membranes with the following primary antibodies: pro-Caspase-1 + p10 + p12 [EPR16883] (Abcam), β-actin (Sigma), NLRP3 [Cryo-2] (Adipogen), all antibody incubations It is implemented in Azure Blot Wash Buffer + 5% Low Fat Milk Powder. The secondary antibody system was purchased from Azure Biosystems. After each antibody was incubated with Azure Blot Wash Buffer, the membrane was washed for at least 3x5 minutes. The membrane was imaged using an Azure c300 imager (Azure Biosystems).result Western blot method Stimulation of BMDM by LPS and Nigerianin successively will cause the activation of NLRP3 inflammasomes, which in turn initiates caspase-1 activation. During autocatalytic cleavage, p45 pro-cystease is cleaved into p10 and p20 fragments. The decrease in intensity of the p45 band attached to the western blot and the presence of the p10 band indicate successful activation of caspase-1 when stimulated by LPS and nicotin. In the presence of 10 μM compounds 1, 4, and 2, blocking the activation of caspase-1 was indicated by the intact p45 band and the lack of the p10 band (Figure 6).Biological examples 9 : Pharmacokinetics in mice The intravenous solution is administered at 1 mg / kg, and is prepared by dissolving the test substance in the formulation shown below. An oral suspension is administered at 10 mg / kg, and is prepared by dissolving a test substance in a formulation shown below. Blood samples were collected into tubes containing K2EDTA or sodium heparin, and kept frozen on ice or wet ice immediately after collection and during processing. After centrifugation, the resulting plasma samples were stored in a refrigerator at -80 ° C until the samples were analyzed. Pharmacokinetic parameters were determined after measuring the concentration of the compound in plasma using standard bioanalytical methods at time points ranging from 0 to 24 hours. Compound A:Compound B:Compound C:Compound D:Compound E: Equivalent content Although the invention has been described in conjunction with the specific embodiments described above, those skilled in the art will appreciate many alternatives, modifications, and other variations. All such alternatives, modifications, and variations are intended to be within the spirit and scope of the invention.

圖1顯示由於經化合物1、化合物2或化合物3治療外周血單核細胞(PBMC)中IL-1β產生之抑制。 圖2顯示由於經化合物1、化合物4或化合物5治療庫弗氏細胞(Kupffer cell，KC)中IL-1β及IL-18產生、而非TNFα產生之抑制。 圖3顯示化合物1及化合物2之LPS及ATP攻擊模型中IL-1β之調節。 圖4顯示化合物1及化合物2之LPS及ATP攻擊模型中TNFα之調節。 圖5顯示化合物3之LPS及ATP攻擊模型中IL-1β之調節。 圖6顯示由於經化合物1、化合物4或化合物2治療半胱天冬酶1之活化(促-半胱天冬酶1轉化成活性半胱天冬酶1)的抑制。Figure 1 shows the inhibition of IL-1β production in peripheral blood mononuclear cells (PBMC) due to treatment with Compound 1, Compound 2, or Compound 3. Figure 2 shows the inhibition of IL-1β and IL-18 production in Kupffer cells (KC), but not TNFα production, as a result of treatment with Compound 1, Compound 4, or Compound 5. Figure 3 shows the regulation of IL-1β in LPS and ATP challenge models of Compound 1 and Compound 2. Figure 4 shows the regulation of TNFα in LPS and ATP challenge models of Compound 1 and Compound 2. Figure 5 shows the regulation of IL-1β in the LPS and ATP challenge models of Compound 3. Figure 6 shows the inhibition of activation of caspase 1 (conversion of caspase-1 to active caspase 1) by treatment with compound 1, compound 4, or compound 2.

Claims (99)

一種式If化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。A compound of formula If, Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X 1 is O or S; R 1 is selected from the group consisting of: among them Represents a single bond or a double bond, provided that the ring containing one or more A 2 is a non-aromatic ring; each A is independently CR 5a1 or N; each A 2 is independently CR 5a2 , C (R 5a2 ) 2 , N, NR 5a2 , O, S or S (O) 2 ; R 2 series or X 2 is N or CR 5b1 ; R 3 and R 4 are H; each R 5a1 is independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -NR 6 C (O) R 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 olefin , C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkane Group; among which C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclic group , Aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 substitution; each R 5a2 is independently H , D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3- C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH 2 -C 3 -C 8 cycloalkyl; those wherein C 1 -C 6 alkyl, C 2 -C 6 Group, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl Base as appropriate via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a 2 and its attached atom may form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 selected from the group consisting of N, S, P and O Group of heteroatoms; wherein the C 3 -C 8 cycloalkyl and heterocyclic groups are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a 2 on the same carbon may form a pendant oxygen group; R 5b1 is H, D, halogen , -CN, -OR 6 or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -C (O) NR 6 , -C (O) OR 6 ; wherein these C 1 -C 6 alkanes And C 3 -C 8 cycloalkyl via D, halogen, -CN, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 substitution; each R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 is independently H, D, halogen, OH,- CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 ring Alkyl and C 2 -C 6 alkynyl via D, halogen, -CN, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) ) 2 substitutions; or two adjacent R 5b2 , R 5b3 , R 5b4 , R 5b5, and R 5b6 together with the atoms to which they are attached may form a C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, Wherein C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl) or - N (C 1 -C 6 alkyl) 2 ; and R 6 and R 7 are independently H, D, C 1 -C 8 alkyl, C 2 -C at each occurrence 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl Base The hetero atom group selected from the group consisting of 1-5 N, S, P and O of the composition; wherein those C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl group, C 3 - C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl and heteroaryl via D, -CN, halogen, C 1 -C 6 alkyl, -OH, -OC 1- C 6 alkyl, -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 substitution; or R 6 and R 7 together with the atom to which they are attached may form a Heterocyclic or heteroaryl groups of 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; provided that the ring system contains A and / or A 1 imidazole, then at least one A 2 N, NR 5a2 , O, S or S (O) 2 . 如請求項1之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中： X1 係O； R1 係選自由以下組成之群：、及； 其中代表單鍵； 每一A2 獨立地係C(R5a2 )2 或O； X2 係CR5b1 ； 每一R5a1 獨立地係H或C1 -C6 烷基；其中該C1 -C6 烷基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基或雜環基；其中該等C1 -C6 烷基及雜環基視情況經D、鹵素、-OR6 、-NH2 、NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 或-S(O)2 -R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素或C1 -C6 烷基； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、-CN、-OR6 、C1 -C6 烷基或C3 -C8 環烷基；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基或雜芳基，其中C3 -C8 環烷基、雜環基或雜芳基視情況經鹵素或C1 -C6 烷基取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 炔基或芳基；其中該等C1 -C8 烷基、C2 -C8 炔基及芳基視情況經D、鹵素或C1 -C6 烷基取代。If the compound of claim 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X 1 is O; R 1 is selected from the group consisting of : , and ; among them Represents a single bond; each A 2 is independently C (R 5a2 ) 2 or O; X 2 is CR 5b1 ; each R 5a1 is independently H or C 1 -C 6 alkyl; wherein the C 1 -C 6 Alkyl via D, halogen, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 substitution; each R 5a2 is independently H, halogen, OH, -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl or heterocyclic Where the C 1 -C 6 alkyl and heterocyclyl optionally pass D, halogen, -OR 6 , -NH 2 , NH (C 1 -C 6 alkyl), N (C 1 -C 6 alkyl 2 ), -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 substitution; or two R 5a 2 together with the atom to which they are attached may form a C 3 -C 8 cycloalkyl or heterocyclic group ; Wherein the heterocyclic group contains 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclic group are optionally passed through D, halogen, C 1- C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 or -S (O) 2 -R 6 substituted ; Or two R 5a2 on the same carbon may form a pendant oxygen group; R 5b1 is H, D, halogen or C 1 -C 6 alkyl; each R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 are independently H, D, halogen, -CN, -OR 6 , C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; wherein these C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl is optionally substituted with D, halogen, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 ; or two R 5b2 , R 5b3 , R 5b4 , R 5b5, and R 5b6 together with the atoms to which they are attached can form a C 3 -C 8 cycloalkyl, heterocyclyl, or heteroaryl, of which C 3 -C 8 cycloalkyl, hetero Cyclic or heteroaryl is optionally substituted with halogen or C 1 -C 6 alkyl; and R 6 and R 7 are independently H, D, C 1 -C 8 alkyl, C 2 -C at each occurrence 8 alkynyl or aryl; wherein these C 1 -C 8 alkyl, C 2 -C 8 alkynyl and aryl are optionally substituted with D, halogen or C 1 -C 6 alkyl. 一種式Ig化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、N(C1 -C6 烷基)2 、 -NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。A compound of formula Ig, Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X 1 is O or S; R 1 is selected from the group consisting of: among them Represents a single bond or a double bond, provided that the ring containing one or more A 2 is a non-aromatic ring; each A is independently CR 5a1 or N; each A 2 is independently CR 5a2 , C (R 5a2 ) 2 , N, NR 5a2 , O, S or S (O) 2 ; R 2 series or X 2 is N or CR 5b1 ; R 3 and R 4 are H; each R 5a1 is independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -NR 6 C (O) R 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 olefin , C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkane Group; among which C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclic group , Aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl), N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 substitution; each R 5a2 is independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aromatic group, heteroaryl, or -CH 2 -C 3 -C 8 cycloalkyl; those wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl , C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl optionally substituted with D, -CN, halo , C 1 -C 6 alkyl, -OR 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a 2 together with the atom to which they are attached may form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 Heteroatoms selected from the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 or -NR 6 S (O ) 2 R 6 substitution; or two R 5a2 on the same carbon may form a pendant oxygen group; R 5b1 is H, D, halogen, -CN, -OR 6 or C 1 -C 6 alkyl, C 3- C 8 cycloalkyl, -C (O) NR 6 , -C (O) OR 6 ; wherein these C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally passed through D, halogen, -CN , -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 substitution; each R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 is independently H, D, halogen, OH, -CN,- NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl and C 2 -C 6 alkynyl is optionally substituted with D, halogen, -CN, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 ; Or two adjacent R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 together with the atom to which they are attached can form a C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl group, where C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally via halogen, -CN, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkane group) or - N (C 1 -C 6 alkyl) 2-substituted; and R 6 and R 7 are independently at each occurrence H lines, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl group , C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl or heteroaryl; wherein these heterocyclic and heteroaryl groups contain 1 To 5 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 ring Group, C 4 -C 8 cycloalkenyl group, heterocyclyl group, aryl and heteroaryl are optionally substituted with D, -CN, halo, C 1 -C 6 alkyl, -OH, -OC 1 -C 6 alkyl , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 substitution; or R 6 and R 7 together with the atom to which they are attached may form a group containing 1 to 3 Heterocyclic group or heteroaryl group selected from heteroatoms of the group consisting of N, S, P, and O; if the ring system contains A and / or A 1 imidazole, then at least one A 2 is N, NR 5a2 , O, S, or S (O) 2 . 一種式Ih化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、-OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 其中至少一個R5a2 係-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。A compound of formula Ih, Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X 1 is O or S; R 1 is selected from the group consisting of: among them Represents a single bond or a double bond, provided that the ring containing one or more A 2 is a non-aromatic ring; each A is independently CR 5a1 or N; each A 2 is independently CR 5a2 , C (R 5a2 ) 2 , N, NR 5a2 , O, S or S (O) 2 ; R 2 series or ; X 2 is N or CR 5b1 ; R 3 and R 4 are H; each R 5a1 is independently H, D, halogen, -OH, -CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -NR 6 C (O) R 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 Cycloalkyl; where the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, hetero Cyclic, aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 substitution; each R 5a2 is independently H, D, halogen, OH, -CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 Cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl Base) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O ) 2 R 6 substitution; or at least one of R 5a2 is -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl or N-containing heterocyclic group, wherein the C 1 -C 6 alkyl is -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 and wherein the heterocyclic group is optionally substituted by D, -CN, halogen, C 1 -C 6 alkyl -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C ( O) R 6 , -NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; R 5b1 is H, D, halogen, -CN,- OR 6 or C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -C (O) NR 6 , -C (O) OR 6 ; wherein these C 1 -C 6 alkyl and C 3- C 8 cycloalkyl is optionally substituted with D, halogen, -CN, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 ; each One R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 are independently H, D, halogen, OH, -CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl or C 2 -C 6 alkynyl; wherein these C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl, and C 2 -C 6 alkynyl via D, halogen, -CN, -OR 6 , -NH 2 ,- NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 substitution; or two adjacent R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 may be together with the atom to which they are attached Forms a C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where the C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally halogen, -CN, C 1- C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or - N (C 1 -C 6 alkyl) 2 substitution; and R 6 and R 7 are Appears independently as H, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl , Heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; wherein Other C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl group, heterocyclyl group, aryl group and Heteroaryl via D, -CN, halogen, C 1 -C 6 alkyl, -OH, -OC 1 -C 6 alkyl, -NH 2 , -NH (C 1 -C 6 alkyl) or- N (C 1 -C 6 alkyl) 2 substitution; or R 6 and R 7 together with the atom to which they are attached may form a heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O Or heteroaryl; provided that when a ring system imidazole containing A and / or A 1 is present, then at least one A 2 is N, NR 5a2 , O, S or S (O) 2 . 一種式Ie化合物，或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物， 其中： X1 係O或S； R1 係選自由以下組成之群：其中代表單鍵或雙鍵，條件係包含一或多個A2 之環係非芳香族環； 每一A獨立地係CR5a1 或N； 每一A2 獨立地係CR5a2 、C(R5a2 )2 、N、NR5a2 、O、S或S(O)2 ； R2 係或； X2 係N或CR5b1 ； 每一Rb10 、Rb11 、Rb12 、Rb13 、Rb14 及Rb15 獨立地係H、-OH或側氧基； R3 及R4 係H； 每一R5a1 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； 每一R5a2 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2 可形成側氧基； R5b1 係H、D、鹵素、-CN、-OR6 或C1 -C6 烷基、C3 -C8 環烷基、-C(O)NR6 、-C(O)OR6 ；其中該等C1 -C6 烷基及C3 -C8 環烷基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代； 每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、-CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基或C2 -C6 炔基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C3 -C8 環烷基及C2 -C6 炔基視情況經D、鹵素、-CN、-OR6 、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 兩個毗鄰R5b2 、R5b3 、R5b4 、R5b5 及R5b6 與其附接之原子一起可形成C3 -C8 環烷基、雜環基、芳基或雜芳基，其中C3 -C8 環烷基、雜環基、芳基或雜芳基視情況經鹵素、-CN、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)或- N(C1 -C6 烷基)2 取代；且 R6 及R7 在每次出現時獨立地係H、D、C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基或雜芳基；其中該等雜環基及雜芳基含有1至5個選自由N、S、P及O組成之群之雜原子；其中該等C1 -C8 烷基、C2 -C8 烯基、C2 -C8 炔基、C3 -C8 環烷基、C4 -C8 環烯基、雜環基、芳基及雜芳基視情況經D、-CN、鹵素、C1 -C6 烷基、-OH、-O-C1 -C6 烷基、-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代；或 R6 及R7 與其附接之原子一起可形成含有1至3個選自由N、S、P及O組成之群之雜原子的雜環基或雜芳基； 條件係在包含A及/或A1 之環係咪唑時，則至少一個A2 係N、NR5a2 、O、S或S(O)2 。A compound of formula Ie, Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein: X 1 is O or S; R 1 is selected from the group consisting of: among them Represents a single bond or a double bond, provided that the ring containing one or more A 2 is a non-aromatic ring; each A is independently CR 5a1 or N; each A 2 is independently CR 5a2 , C (R 5a2 ) 2 , N, NR 5a2 , O, S or S (O) 2 ; R 2 series or X 2 is N or CR 5b1 ; each R b10 , R b11 , R b12 , R b13 , R b14 and R b15 is independently H, -OH or pendant oxygen; R 3 and R 4 are H; each R 5a1 is independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -NR 6 C (O) R 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 olefins , C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 cycloalkane Base as appropriate via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 substitution; each R 5a2 is independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl , Aryl, heteroaryl, or -CH 2 -C 3 -C 8 cycloalkyl; those wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a2 attached to it The atoms together can form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 -cycloalkyl and heterocyclyl via D, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 or- NR 6 S (O) 2 R 6 substitution; or two R 5a2 on the same carbon can form side oxygen; R 5b1 is H, D, halogen, -CN, -OR 6 or C 1 -C 6 alkane Group, C 3 -C 8 cycloalkyl, -C (O) NR 6 , -C (O) OR 6 ; of which C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl optionally pass D, halogen, -CN, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1- C 6 alkyl) 2 substitutions; each R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 is independently H, D, halogen, OH, -CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl, or C 2 -C 6 alkynyl; of which C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl, and C 2 -C 6 alkynyl, as appropriate Substituted by D, halogen, -CN, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 ; or two adjacent R 5b2 , R 5b3, R 5b4, R 5b5 and R 5b6 of atoms may be attached thereto together form a C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the C 3 -C 8 cycloalkyl, heterocyclyl Aryl, aryl or heteroaryl optionally via halogen, -CN, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl) or - N (C 1- C 6 alkyl) 2 substitution; and R 6 and R 7 are independently H, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1 to 5 heteroatoms selected from the group consisting of N, S, P and O; wherein The C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl And heteroaryl via D, -CN, halogen, C 1 -C 6 alkyl, -OH, -OC 1 -C 6 alkyl, -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 substitution; or R 6 and R 7 together with the atom to which they are attached may form a hetero group containing 1 to 3 heteroatoms selected from the group consisting of N, S, P, and O A cyclic or heteroaryl group; if the ring is imidazole containing A and / or A 1 , then at least one A 2 is N, NR 5a2 , O, S or S (O) 2 . 如請求項1及3至5中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中X1 係O。The compound of any one of claims 1 and 3 to 5 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein X 1 is O. 如請求項1至6中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項7之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中X2 係CR5b1 。For example, the compound of claim 7 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein X 2 is CR 5b1 . 如請求項8之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5b1 係H、鹵素或C1 -C6 烷基。For example, the compound of claim 8 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 5b1 is H, halogen or C 1 -C 6 alkyl. 如請求項8之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5b1 係H、氟、氯或甲基。For example, the compound of claim 8 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 5b1 is H, fluorine, chlorine or methyl. 如請求項1至10中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項1至10中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項1至6中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項13之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地係H、D、鹵素、OH、CN、-NO2 、-OR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基或C3 -C8 環烷基。If the compound of claim 13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each of R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 is independently H, D, halogen, OH, CN, -NO 2 , -OR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl or C 3- C 8 cycloalkyl. 如請求項1至13中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項15之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5b2 、R5b3 、R5b4 、R5b5 及R5b6 獨立地選自由H、D、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN組成之群。If the compound of claim 15 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, each of R 5b2 , R 5b3 , R 5b4 , R 5b5 and R 5b6 is independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and -CN. 如請求項1至16中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係選自由以下組成之群：及。The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is selected from the group consisting of : and . 如請求項1至17中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係選自由以下組成之群：及。The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is selected from the group consisting of : and . 如請求項1至18中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項1至13中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項20之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5b2 及R5b4 係選自由以下組成之群：H、D、鹵素、C1 -C6 烷基、C3 -C8 環烷基及-CN。If the compound of claim 20 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each of R 5b2 and R 5b4 is selected from the group consisting of: H, D, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and -CN. 如請求項20及21中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R2 係。The compound of any one of claims 20 and 21 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 2 is . 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係或。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is or . 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係、或。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is , or . 如請求項1至24中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。If the compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, one of the A is CR 5a1 and the other A Department N. 如請求項1至25中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each A 2 is independently C ( R 5a2 ) 2 , NR 5a2 or O. 如請求項26之化合物，其中每一R5a2 獨立地係H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代。The compound of claim 26, wherein each R 5a2 is independently H, -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, or N-containing heterocyclic group, wherein the C 1 -C 6 alkyl Group is substituted with -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 , and wherein the heterocyclic group is optionally substituted with D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or- NR 6 C (O) R 6 , -NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 are substituted. 如請求項27之化合物，其中R1 係選自由以下組成之群：及； 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代，且 R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地選自H、-NHR6 、-NR6 R7 、C1 -C6 烷基或含N之雜環基，其中該C1 -C6 烷基經-NH2 、-NH(C1 -C6 烷基)或-N(C1 -C6 烷基)2 取代，且其中該雜環基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 、-NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代。The compound of claim 27, wherein R 1 is selected from the group consisting of: and ; Where R 5a1a is H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -NR 6 C (O) R 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 olefins , C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 cycloalkane Base as appropriate via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 is substituted and R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e and R 5a2f are independently selected from H, -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl or N-containing heterocyclic group, wherein the C 1 -C 6 alkyl is -NH 2 , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) 2 and wherein the heterocyclic group is optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 is substituted. 如請求項1至23中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is . 如請求項29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。For example, the compound of claim 29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein one A is CR 5a1 and the other A is N. 如請求項29至30中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。The compound of any one of claims 29 to 30 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each A 2 is independently C ( R 5a2 ) 2 , NR 5a2 or O. 如請求項29至30中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。If the compound of any one of claims 29 to 30 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R 5a2 is independently H, Halogen, OH, -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2- C 3 -C 8 cycloalkyl. 如請求項20至32中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中兩個R5a2 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。A compound according to any one of claims 20 to 32 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, in which two R 5a 2 and the atom to which it is attached Together, they can form a C 3 -C 8 cycloalkyl or heterocyclyl. 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ；且 A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 可形成側氧基。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is , Which has the formula Where A 2ab is selected from CR 5a2 , C (R 5a2a ) (R 5a2b ), N, NR 5a2 , O, S, or S (O) 2 ; A 2cd is selected from CR 5a2 , C (R 5a2c ) (R 5a2d ), N, NR 5a2 , O, S, or S (O) 2 ; A 2ef is selected from CR 5a2 , C (R 5a2e ) (R 5a2f ), N, NR 5a2 , O, S, or S (O) 2 ; And A 2gh is selected from CR 5a2 , C (R 5a2g ) (R 5a2h ), N, NR 5a2 , O, S, or S (O) 2 ; each R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g and R 5a2h are independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 ring Alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O ) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g, and R 5a2h together with the atoms to which they are attached may form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 members selected from N, S, P, and A heteroatom of a group consisting of O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O ) R 6 , -NR 6 C (O) NR 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g and R 5a2h may form pendant oxygen groups. 如請求項34之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 其中R5a1a 係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-NR6 C(O)R6 、-NR6 C(O)OR6 、-NR6 C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 或-NR6 C(O)R6 取代； R5a2c 及R5a2d 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH( C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 可形成側氧基。The compound of claim 34 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is Where R 5a1a is H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -NR 6 C (O) R 6 , -NR 6 C (O) OR 6 , -NR 6 C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl , C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1 -C 6 alkyl, C 2 -C 6 Alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH 2 -C 3 -C 8 ring Alkyl via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) ) 2 , -NR 6 C (O) OR 6 or -NR 6 C (O) R 6 substitution; R 5a2c and R 5a2d are each independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl Or -CH 2 -C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH ( C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 ,- NR 6 C (O) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 ; or R 5a2c and R 5a2d attached to it The atoms together can form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 -cycloalkyl and heterocyclyl via D, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 or- NR 6 S (O) 2 R 6 is substituted; or R 5a2c and R 5a2d may form a pendant oxygen group. 如請求項35之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。If the compound of claim 35 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each of R 5a2c and R 5a2d is independently H, halogen, OH , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3- C 8 cycloalkyl. 如請求項35至36中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。If the compound of any one of claims 35 to 36 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 5a2c and R 5a2d are attached to it The atoms together can form a C 3 -C 8 cycloalkyl or heterocyclyl. 如請求項34之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 R5a2a 及R5a2b 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2a 及R5a2b 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2a 及R5a2b 可形成側氧基。The compound of claim 34 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is Where R 5a2a and R 5a2b are each independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl , C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 cycloalkyl via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or R 5a2a and R 5a2b together with the atom to which they are attached may form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 Heteroatoms of the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 ,- NH 2, -NH (C 1 -C 6 alkyl), - N (C 1 -C 6 alkyl) 2 -S (O) 2 -R 6, -COR 6, NR 6 C (O) OR 6, -NR 6 C (O) R 6, -NR 6 C (O) NR 6 , or -NR 6 S (O) 2 R 6 is substituted; or R 5a2a and R 5a2b may form a pendant oxy group. 如請求項38之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2a 及R5a2b 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。If the compound of claim 38 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each of R 5a2a and R 5a2b is independently H, halogen, OH , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3- C 8 cycloalkyl. 如請求項38至39中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2a 及R5a2b 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。If the compound of any one of claims 38 to 39 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 5a2a and R 5a2b are attached to it The atoms together can form a C 3 -C 8 cycloalkyl or heterocyclyl. 如請求項33之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 R5a2e 及R5a2f 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2e 及R5a2f 可形成側氧基。The compound of claim 33 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is Where R 5a2e and R 5a2f are each independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl , C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 cycloalkyl via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or R 5a2e and R 5a2f together with the atom to which they are attached may form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 Heteroatoms of the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 ,- NH 2, -NH (C 1 -C 6 alkyl), - N (C 1 -C 6 alkyl) 2 -S (O) 2 -R 6, -COR 6, NR 6 C (O) OR 6, -NR 6 C (O) R 6, -NR 6 C (O) NR 6 , or -NR 6 S (O) 2 R 6 is substituted; or R 5a2e and R 5a2f may form a pendant oxy group. 如請求項41之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2e 及R5a2f 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。If the compound of claim 41 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each of R 5a2e and R 5a2f is independently H, halogen, OH , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3- C 8 cycloalkyl. 如請求項41至42中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。If the compound of any one of claims 41 to 42 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 5a2e and R 5a2f are attached to it The atoms together can form a C 3 -C 8 cycloalkyl or heterocyclyl. 如請求項34之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其中 R5a2c 及R5a2d 各自獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH( C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 R5a2c 及R5a2d 可形成側氧基。The compound of claim 34 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is Where R 5a2c and R 5a2d are each independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl , C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH ( C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or R 5a2c and R 5a2d together with the atom to which they are attached may form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 Heteroatoms of the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 ,- NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 or -NR 6 S (O ) 2 R 6 substituted; or R 5a2c and R 5a2d may form a pendant oxy group. 如請求項44之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一R5a2c 及R5a2d 獨立地係H、鹵素、OH、-OR6 、-NHR6 、-NR6 R7 、C1 -C6 烷基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基。If the compound of claim 44 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each of R 5a2c and R 5a2d is independently H, halogen, OH , -OR 6 , -NHR 6 , -NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3- C 8 cycloalkyl. 如請求項44至45中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R5a2c 及R5a2d 與其附接之原子一起可形成C3 -C8 環烷基或雜環基。If the compound of any one of claims 44 to 45 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 5a2c and R 5a2d are attached to it The atoms together can form a C 3 -C 8 cycloalkyl or heterocyclyl. 如請求項29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係選自由以下組成之群： The compound of claim 29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is selected from the group consisting of: 如請求項29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係選自由以下組成之群：。The compound of claim 29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is selected from the group consisting of: . 如請求項29之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係選自由以下組成之群：。The compound of claim 29 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is selected from the group consisting of: . 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is . 如請求項50之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。For example, a compound of claim 50 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein one A is CR 5a1 and the other A is N. 如請求項50至51中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。A compound according to any one of claims 50 to 51 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each A 2 is independently C ( R 5a2 ) 2 , NR 5a2 or O. 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ；且 A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； A2ij 係選自CR5a2 、C(R5a2i )(R5a2j )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 、R5a2h 、R5a2i 及R5a2j 可形成側氧基。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is , Which has the formula Where A 2ab is selected from CR 5a2 , C (R 5a2a ) (R 5a2b ), N, NR 5a2 , O, S, or S (O) 2 ; A 2cd is selected from CR 5a2 , C (R 5a2c ) (R 5a2d ), N, NR 5a2 , O, S, or S (O) 2 ; A 2ef is selected from CR 5a2 , C (R 5a2e ) (R 5a2f ), N, NR 5a2 , O, S, or S (O) 2 And A 2gh is selected from CR 5a2 , C (R 5a2g ) (R 5a2h ), N, NR 5a2 , O, S, or S (O) 2 ; A 2ij is selected from CR 5a2 , C (R 5a2i ) (R 5a2j ), N, NR 5a2 , O, S, or S (O) 2 ; each R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g , R 5a2h , R 5a2i, and R 5a2j are independent Earth system H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 olefins , C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2 -C 3 -C 8 cycloalkane are optionally substituted with D, -CN, halo, C 1 -C 6 Group, -OR 6, -NH 2, -NH (C 1 -C 6 alkyl), - N (C 1 -C 6 alkyl) 2, -NR 6 C (O ) OR 6, -NR 6 C ( O) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g , R 5a2h , R 5a2i, and R 5a2j together with the atoms to which they are attached can form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 options Heteroatoms of the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 ,- NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a2a , R 5a2b , R 5a2c on the same carbon , R 5a2d , R 5a2e , R 5a2f , R 5a2g , R 5a2h , R 5a2i, and R 5a2j can form pendant oxygen groups. 如請求項50之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。The compound of claim 50 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is . 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is . 如請求項55之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。For example, the compound of claim 55 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein one A is CR 5a1 and the other A is N. 如請求項55至56中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。The compound of any one of claims 55 to 56 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each A 2 is independently C ( R 5a2 ) 2 , NR 5a2 or O. 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自C(R5a2a )(R5a2b )、NR5a2 、O、S或S(O)2 ； A2cd 係選自C(R5a2c )(R5a2d )、NR5a2 、O、S或S(O)2 ； A2ef 係選自C(R5a2e )(R5a2f )、NR5a2 、O、S或S(O)2 ；且 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代；或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代；或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 及R5a2f 可形成側氧基。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is , Which has the formula Where A 2ab is selected from C (R 5a2a ) (R 5a2b ), NR 5a2 , O, S or S (O) 2 ; A 2cd is selected from C (R 5a2c ) (R 5a2d ), NR 5a2 , O, S or S (O) 2 ; A 2ef is selected from C (R 5a2e ) (R 5a2f ), NR 5a2 , O, S or S (O) 2 ; and each R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e and R 5a2f are independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 ,- S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1 -C 6 alkyl , C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and -CH 2- C 3 -C 8 cycloalkyl via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substituents; or two R 5a2a, R 5a2b, R 5a2c , R 5a2d, R 5a2e attached thereto, and R 5a2f The atoms together may form a C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclic group containing a hetero atom of the group selected from the group consisting of 1-3 N, S, P and O of the composition; wherein such C 3 - C 8 cycloalkyl and heterocyclyl optionally pass D, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1- C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O) R 6 , -NR 6 C (O) NR 6 or -NR 6 S (O) 2 R 6 substitution; or two R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e, and R 5a2f on the same carbon may form a pendant oxygen group. 如請求項55之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。The compound of claim 55 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is . 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is . 如請求項60之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中一個A係CR5a1 且另一A係N。For example, the compound of claim 60 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein one A is CR 5a1 and the other A is N. 如請求項60至61中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中每一A2 獨立地係C(R5a2 )2 、NR5a2 或O。The compound of any one of claims 60 to 61 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each A 2 is independently C ( R 5a2 ) 2 , NR 5a2 or O. 如請求項1至22中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中R1 係，其具有式，其中 A2ab 係選自CR5a2 、C(R5a2a )(R5a2b )、N、NR5a2 、O、S或S(O)2 ； A2cd 係選自CR5a2 、C(R5a2c )(R5a2d )、N、NR5a2 、O、S或S(O)2 ； A2ef 係選自CR5a2 、C(R5a2e )(R5a2f )、N、NR5a2 、O、S或S(O)2 ；且 A2gh 係選自CR5a2 、C(R5a2g )(R5a2h )、N、NR5a2 、O、S或S(O)2 ； 每一R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 獨立地係H、D、鹵素、OH、CN、-NO2 、-SR6 、-OR6 、-NHR6 、-NR6 R7 、-C(O)R6 、-S(O)2 R6 、-C(O)OR6 、-C(O)NR6 、C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基或-CH2 -C3 -C8 環烷基；其中該等C1 -C6 烷基、C2 -C6 烯基、C4 -C8 環烯基、C2 -C6 炔基、C3 -C8 環烷基、雜環基、芳基、雜芳基及-CH2 -C3 -C8 環烷基視情況經D、-CN、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-NR6 C(O)OR6 、-NR6 C(O)R6 、NR6 C(O)NR6 、-NR6 C(O)R6 或-NR6 S(O)2 R6 取代，或 兩個R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 與其附接之原子一起可形成C3 -C8 環烷基或雜環基；其中該雜環基含有1至3個選自由N、S、P及O組成之群之雜原子；其中該等C3 -C8 環烷基及雜環基視情況經D、鹵素、C1 -C6 烷基、-OR6 、-NH2 、-NH(C1 -C6 烷基)、-N(C1 -C6 烷基)2 、-S(O)2 -R6 、-COR6 、NR6 C(O)OR6 、-NR6 C(O)R6 、-NR6 C(O)NR6 或-NR6 S(O)2 R6 取代，或 兩個在同一個碳上之R5a2a 、R5a2b 、R5a2c 、R5a2d 、R5a2e 、R5a2f 、R5a2g 及R5a2h 可形成側氧基。The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R 1 is , Which has the formula Where A 2ab is selected from CR 5a2 , C (R 5a2a ) (R 5a2b ), N, NR 5a2 , O, S, or S (O) 2 ; A 2cd is selected from CR 5a2 , C (R 5a2c ) (R 5a2d ), N, NR 5a2 , O, S, or S (O) 2 ; A 2ef is selected from CR 5a2 , C (R 5a2e ) (R 5a2f ), N, NR 5a2 , O, S, or S (O) 2 ; And A 2gh is selected from CR 5a2 , C (R 5a2g ) (R 5a2h ), N, NR 5a2 , O, S, or S (O) 2 ; each R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g and R 5a2h are independently H, D, halogen, OH, CN, -NO 2 , -SR 6 , -OR 6 , -NHR 6 , -NR 6 R 7 , -C (O) R 6 , -S (O) 2 R 6 , -C (O) OR 6 , -C (O) NR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 ring Alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH 2 -C 3 -C 8 cycloalkyl; wherein these C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH 2 -C 3 -C 8 cycloalkyl optionally via D, -CN, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -NR 6 C (O) OR 6 , -NR 6 C (O ) R 6 , NR 6 C (O) NR 6 , -NR 6 C (O) R 6 or -NR 6 S (O) 2 R 6 substitution, or two R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g, and R 5a2h together with the atoms to which they are attached may form a C 3 -C 8 cycloalkyl or heterocyclic group; wherein the heterocyclic group contains 1 to 3 members selected from N, S, P, and A heteroatom of a group consisting of O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally passed through D, halogen, C 1 -C 6 alkyl, -OR 6 , -NH 2 , -NH (C 1- C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , -S (O) 2 -R 6 , -COR 6 , NR 6 C (O) OR 6 , -NR 6 C (O ) R 6 , -NR 6 C (O) NR 6 or -NR 6 S (O) 2 R 6 substitution, or two R 5a2a , R 5a2b , R 5a2c , R 5a2d , R 5a2e , R 5a2f , R 5a2g and R 5a2h may form pendant oxygen groups. 如請求項1至63中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其中該等係包含A2 之環中之單鍵，藉此形成飽和環。A compound according to any one of claims 1 to 63 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein these Is a single bond in the ring of A 2 , thereby forming a saturated ring. 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其係選自由以下組成之群： 。A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, which is selected from the group consisting of: . 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其係選自由以下組成之群： 。A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, which is selected from the group consisting of: . 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其係選自由以下組成之群：。A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, which is selected from the group consisting of: . 一種化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其係選自由以下組成之群： 。A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, which is selected from the group consisting of: . 一種醫藥組合物，其包含如請求項1至68中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物以及醫藥上可接受之載劑。A pharmaceutical composition comprising the compound according to any one of claims 1 to 68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, and a pharmaceutically acceptable Accepted vehicle. 一種治療或預防對發炎體之抑制有反應之疾病、病症或病況的方法，其包括投與有效量之如請求項1至68中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，為有此需要之個體治療或預防該疾病、病症或病況。A method for treating or preventing a disease, disorder or condition responsive to the inhibition of an inflammable body, which comprises administering an effective amount of a compound according to any one of claims 1 to 68 or a pharmaceutically acceptable salt, prodrug , Solvates, hydrates, isomers, or tautomers, are individuals in need thereof to treat or prevent the disease, disorder, or condition. 如請求項70之方法，其中該疾病、病症或病況係對NLRP3發炎體之活化之抑制有反應者。The method of claim 70, wherein the disease, disorder, or condition is a responder to inhibition of activation of the NLRP3 inflammasome. 如請求項70或71之方法，其中該疾病、病症或病況對IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞中之一或多者之調節有反應。The method of claim 70 or 71, wherein the disease, disorder or condition affects IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33 and Th17 The regulation of one or more of the cells is responsive. 如請求項70或71之方法，其中該疾病、病症或病況對IL-1β及IL-18中之一或多者之調節有反應。The method of claim 70 or 71, wherein the disease, disorder, or condition is responsive to the modulation of one or more of IL-1β and IL-18. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係免疫系統之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係發炎性疾病、病症或病況或自體免疫疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition, or an autoimmune disease, disorder, or condition. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係肝之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the liver. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係肺之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the lung. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係皮膚之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the skin. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係心血管系統之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係癌症、腫瘤或其他惡性病。The method of any one of claims 70 to 73, wherein the disease, disorder or condition is cancer, tumor or other malignant disease. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係腎系統之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the renal system. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係胃腸道之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the gastrointestinal tract. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係呼吸系統之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係內分泌系統之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the endocrine system. 如請求項70至73中任一項之方法，其中該疾病、病症或病況係中樞神經系統(CNS)之疾病、病症或病況。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS). 如請求項70至73中任一項之方法，其中該疾病、病症或病況係選自由以下組成之群：組成型發炎、隱熱蛋白相關週期症候群(CAPS)、穆-韋二氏症候群(Muckle-Wells syndrome，MWS)、家族性冷因性自體發炎症候群(FCAS)、新生兒發作性多系統發炎性疾病(NOMID)、自體發炎性疾病、家族性地中海熱(FMF)、TNF受體相關之週期性症候群(TRAPS)、甲羥戊酸激酶缺乏症(MKD)、高免疫球蛋白血症D、週期性發熱症候群(HIDS)、介白素1受體拮抗劑缺乏(DIRA)、馬吉德症候群(Majeed syndrome)、化膿性關節炎、壞疽性膿皮症及痤瘡(PAPA)、A20之單一對偶基因不足性(HA20)、兒科肉芽腫關節炎(PGA)、PLCG2相關之抗體缺乏症及免疫失調(PLAID)、PLCG2相關之自體發炎、抗體缺乏及免疫失調(APLAID)、鐵粒幼細胞性貧血伴B細胞免疫缺乏、週期性發熱、發育遲緩(SIFD)、史維特氏症候群(Sweet's syndrome)、慢性非細菌性骨髓炎(CNO)、慢性復發性多病灶骨髓炎(CRMO)及滑膜炎、痤瘡、膿疱病、骨肥大、骨炎症候群(SAPHO)；自體免疫疾病，包括多發性硬化(MS)、1型糖尿病、牛皮癬、類風濕性關節炎、貝賽特氏病(Behcet's disease)、休格倫氏症候群(Sjogren's syndrome)、薛尼茲勒氏症候群(Schnitzler syndrome)；呼吸疾病、特發性肺纖維化(IPF)、慢性阻塞性肺病症(COPD)、類固醇抗性氣喘、石棉肺、矽肺、囊性纖維化、中樞神經系統疾病、帕金森氏病(Parkinson's disease)、阿茲海默氏病(Alzheimer's disease)、運動神經元疾病、杭丁頓氏病(Huntington's disease)、腦型瘧疾、來自肺炎球菌腦膜炎之腦損傷、代謝疾病、2型糖尿病、動脈粥樣硬化、肥胖症、痛風、假性痛風、眼睛疾病、眼上皮疾病、年齡相關性黃斑退化(AMD)、角膜感染、眼色素層炎、乾眼、腎病、慢性腎病、草酸鹽腎病變、糖尿病腎病變、肝病、非酒精性脂肪性肝炎、酒精性肝病、皮膚之發炎反應、接觸過敏、曬傷、關節之發炎反應、骨關節炎、全身性青少年型特發性關節炎、成人發作性史迪爾氏病(Still's disease)、復發性多發性軟骨炎、病毒感染、α病毒感染、屈公病病毒(Chikungunya virus)感染、羅氏河病毒(Ross River virus)感染、黃病毒感染、登革熱病毒(Dengue virus)感染、茲卡病毒(Zika virus)感染、流行性感冒、HIV感染、化膿性汗腺炎(HS)、囊腫引起之皮膚病、癌症、肺癌轉移、胰臟癌、胃癌、脊髓發育不良症候群、白血病、多發性肌炎、中風、心肌梗塞、移植物抗宿主病、高血壓、結腸炎、蠕蟲感染、細菌感染、腹主動脈瘤、傷口癒合、抑鬱症、心理應激壓力、心包炎、卓斯勒症候群(Dressler's syndrome)、缺血性再灌注損傷、及經判定帶有NLRP3之生殖細胞系或體細胞非靜默突變之個體的任何疾病。The method of any one of claims 70 to 73, wherein the disease, disorder, or condition is selected from the group consisting of: constitutive inflammation, cryptothermia-associated cycle syndrome (CAPS), Mu-Wei's syndrome (Muckle -Wells syndrome (MWS), familial cold-induced autoinflammation syndrome (FCAS), neonatal onset multi-system inflammatory disease (NOMID), auto-inflammatory disease, familial Mediterranean fever (FMF), TNF receptor Associated Periodic Syndrome (TRAPS), Mevalonate Kinase Deficiency (MKD), Hyperimmunoglobulinemia D, Periodic Fever Syndrome (HIDS), Interleukin-1 Receptor Antagonist Deficiency (DIRA), Majid Syndrome (Majeed syndrome), septic arthritis, pyoderma gangrenosum and acne (PAPA), single dual gene deficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency and immunity Disorders (PLAID), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), neutrophilic anemia with B-cell immune deficiency, periodic fever, delayed development (SIFD), Sweet's syndrome ), Chronic non-bacterial bone Inflammation (CNO), chronic relapsing multifocal osteomyelitis (CRMO) and synovitis, acne, pustular disease, osteoporosis, osteoinflammatory syndrome (SAPHO); autoimmune diseases, including multiple sclerosis (MS), type 1 Diabetes, Psoriasis, Rheumatoid Arthritis, Behcet's disease, Sjogren's syndrome, Schnitzler syndrome; respiratory disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestos lung, silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease disease), motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, metabolic disease, type 2 diabetes, atherosclerosis, obesity, gout, pseudosexuality Gout, eye disease, ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic kidney disease, oxalate nephropathy, diabetic nephropathy, liver disease, non- Severe steatohepatitis, alcoholic liver disease, skin inflammatory response, contact allergy, sunburn, joint inflammatory response, osteoarthritis, systemic adolescent idiopathic arthritis, adult-onset Still's disease (Still's disease), relapsing polychondritis, viral infection, alpha virus infection, Chikungunya virus infection, Ross River virus infection, flavivirus infection, dengue virus infection, Zika virus infection, influenza, HIV infection, pyogenic sweat glanditis (HS), dermatosis caused by cysts, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, spinal dysplasia syndrome, leukemia, multiple muscles Inflammation, stroke, myocardial infarction, graft-versus-host disease, hypertension, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Drusler syndrome ( Dressler's syndrome), ischemic reperfusion injury, and any disease in individuals who have been determined to have a non-silent mutation in a germline cell line or somatic cell of NLRP3. 如請求項86之方法，其中該病症係選自由以下組成之群：細菌感染、病毒感染、真菌感染、發炎性腸病、乳糜瀉、結腸炎、腸增生、癌症、代謝症候群、肥胖症、類風濕性關節炎、肝病、肝臟脂肪變性、脂肪肝病、肝纖維化、非酒精性脂肪肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)。The method of claim 86, wherein the disorder is selected from the group consisting of: bacterial infection, viral infection, fungal infection, inflammatory bowel disease, coeliac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, anaemia Rheumatoid arthritis, liver disease, liver steatosis, fatty liver disease, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). 如請求項87之方法，其中該病症係非酒精性脂肪性肝炎(NASH)。The method of claim 87, wherein the condition is non-alcoholic steatohepatitis (NASH). 如請求項70至88中任一項之方法，其中係對哺乳動物進行該疾病、病症或病況之治療或預防。The method of any one of claims 70 to 88, wherein the mammal is treated or prevented for the disease, disorder or condition. 如請求項89之方法，其中該哺乳動物係人類個體。The method of claim 89, wherein the mammal is a human individual. 一種調節生物靶標之活性之方法，其包括將該生物靶標暴露於如請求項1至68中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物的步驟。A method for modulating the activity of a biological target, comprising exposing the biological target to a compound according to any one of claims 1 to 68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomerization thereof Or tautomers. 如請求項91之方法，其中該生物靶標可選自由以下組成之群：NLRP3發炎體、IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞。The method of claim 91, wherein the biological target can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, and IL-22 , IL-33 and Th17 cells. 如請求項91之方法，其中該生物靶標可選自由以下組成之群：IL-1β及IL-18。The method of claim 91, wherein the biological target is selected from the group consisting of IL-1β and IL-18. 一種抑制發炎體之活化之方法，其包括將生物靶標暴露於如請求項1至68中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物的步驟。A method for inhibiting the activation of an inflammable body, comprising exposing a biological target to a compound according to any one of claims 1 to 68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer thereof Or tautomers. 如請求項94之方法，其中該發炎體係NLRP3發炎體。The method of claim 94, wherein the inflammation system NLRP3 is inflamed. 如請求項94或95之方法，其中發炎體之抑制與IL-6、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-22、IL-33及Th17細胞中之一或多者相關。The method of claim 94 or 95, wherein the inhibition of the inflammasome is related to IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33 and Th17 cells One or more of them are related. 如請求項96之方法，其中發炎體之抑制與IL-1β及IL-18中之一或多者相關。The method of claim 96, wherein the inhibition of the inflammasome is associated with one or more of IL-1β and IL-18. 一種如請求項1至68中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物的用途，其用於治療對發炎體之抑制有反應的疾病、病症或病況。A compound as claimed in any one of claims 1 to 68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof for use in treating an inflamed body It inhibits a responsive disease, disorder, or condition. 一種如請求項1至68中任一項之化合物或其醫藥上可接受之鹽、前藥、溶劑合物、水合物、異構物或互變異構物，其用於製造供治療對發炎體之抑制有反應之疾病、病症或病況的藥劑。A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, for use in the manufacture of an inflamed body for treatment An agent that inhibits a responsive disease, disorder, or condition.
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